Paul S. Hammer, MD
Captain, Medical Corps, US Navy; Navy Medicine
Information Systems Support Activity, San Antonio, TX
William M. Sauvé, MD
Medical Director, TMS NeuroHealth Centers of Richmond, VA
Disclosure: This article discusses off-label medication use. Dr. Hammer reports no affiliations with, or financial interests in, any organization that may pose a conflict of interest. Dr. Sauvé has received speaker fees from Sunovion; and has served on the advisory board of Avanir.
This article reviews the unique therapeutic challenges associated with treating military-related brain injury with and without comorbid posttraumatic stress disorder. Specific symptoms, including anxiety symptoms, re-experiencing symptoms, sleep disturbance, and affective symptoms may be targeted discretely.
Healthcare providers face unique challenges when treating service members wounded in Operations Iraqi Freedom and Enduring Freedom. The predominant enemy tactic of improvised explosive devices (IED) and a long war have presented the military healthcare system with large numbers of patients with the two “signature wounds” of the war: mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD).1 These disorders often co-occur and require awareness of the subtleties and comorbidities of both diagnoses in order to appropriately identify, diagnose, and treat the service member. Furthermore, the unpredictable nature of IED attacks not only lead to chronic, sub-acute combat stress but can also result in numerous bodily injuries, sometimes resulting in physical disability and chronic pain. Wounded service members will often see numerous specialists and receive treatment with numerous classes of drugs meant to address chronic pain, sleep difficulty, and affective and anxiety symptoms related to multiple comorbidities. The potential of such medications to work at cross purposes with each other makes it all the more important that healthcare providers become experts in the psychopharmacology involved in both PTSD and mTBI. In addition, the high utilization of National Guard and Reserve forces in active combat ensure that many service members who need or seek care may not be seen in the Veterans Affairs (VA) or Department of Defense (DoD) medical systems. It is therefore imperative that all clinicians, and especially psychiatrists, military and civilian, maintain an awareness of combat-related PTSD, its co-occurrence with mTBI, and an understanding of the principles of medication management available to effectively treat this population.
Military life can be quite stressful, and deployments pose many stresses upon the service members, and the family to which they return following deployment.2 During a deployment to a combat environment, service members are exposed to many potentially traumatic events, and the more events the service member is exposed to the greater the risk of developing PTSD.3
PTSD is a disorder that may occur following an event in which an individual is exposed to serious threat of injury or death, and experiences extreme fear, helplessness, or horror in response to the event. In addition to the essential feature of having experienced a traumatic event, the individual also suffers from episodes in which the event is re-experienced, hyperarousal, avoidance, and numbing of responsiveness. Symptoms must be present for at least 30 days. If left untreated, the individual can have significant problems interacting socially, connecting with people, and maintaining employment.4
A population-based descriptive study found that 19.1% of service members returning from Iraq and 11.3% from Afghanistan reported a psychological health problem.5 Another study, wherein military service members were surveyed 3–4 months following their return from deployment in Iraq and Afghanistan, found that 12.6%–18.9% and 6.2%–11.5%, respectively, met criteria for PTSD, depending on the definition of diagnosis used.3
PTSD can present many negative health effects, including adverse psychosocial consequences.2 A study conducted by the VA highlighted that 20% of patients seen in VA primary care clinics had screened positive for PTSD, yet only 7% had a DSM-IV-based diagnosis in their health record.6 Early intervention increases the likelihood of treatment success, because intervention can occur before work and personal relationships are affected, before comorbid conditions develop, and before secondary maladaptive coping takes place (ie, increased substance use and high-risk taking behavior).7
PTSD AND CO-OCCURING DISORDERS
PTSD is marked by both heterogeneity of symptoms and significant symptom overlap with other disorders. PTSD also displays a variable course that is often complicated by comorbid alcohol abuse, depression, and traumatic brain injury.4 A significant association has been found between PTSD severity and poorer health functioning across domains of physical functioning, role functioning, bodily pain, general health, and health transition. This was found even after accounting for demographic factors, combat and chemical exposure, and health risk behaviors. A study assessing 2,863 soldiers one year after they returned from deployment in Iraq found evidence for a strong relationship between PTSD and functional impairments.8 Specifically, PTSD was significantly associated with lower ratings of general health, more sick call visits, more missed workdays, more physical symptoms, and high somatic symptom severity, after controlling for being wounded or injured.8
The co-morbidity of alcohol use is of particular concern. Service members with at least one deployment have increased rates of heavy weekly drinking, binge drinking, and other alcohol-related problems. Reserve and Guard deployers are at significantly higher risk compared to those who had not deployed.9 Even in the general population, where the prevalence of PTSD from non combat-related trauma is 7.8%, 52% of men and 28% of women with PTSD have problematic alcohol use.10
Traumatic Brain Injury
The issue of comorbidity has been complicated further in the past decade by the conflicts in Iraq and Afghanistan. The predominant enemy tactic of using IEDs has resulted in a large number of deployed service members who have experienced blast and other head injuries. In a study of 7,909 marines with the 1st Marine division at Camp Pendleton, 10% were found to have suffered brain injuries. Out of 161 Marines who suffered concussions, 84% reported that they were still suffering symptoms an average of 10 months after the injury.11
The VA-DoD TBI task force defines a TBI as a traumatically induced structural injury or disruption of brain function which is the result of an external force as indicated by altered consciousness, memory loss, altered mental state, or neurological deficits.12 The severity of TBI is classified as mild, moderate, or severe depending on the Glasgow Coma Scale score, time of loss of consciousness, and duration of post-traumatic amnesia.12 Moderate and severe TBIs are usually clearly evident to both layman and clinician. Symptoms can be physical—headache, dizziness, fatigue, noise/light intolerance, insomnia; cognitive (memory complaints, poor concentration); and emotional (depression, anxiety, irritability, and mood lability).4
The difficulty comes with accurately and effectively diagnosing a mild TBI or concussion. Post Concussion Syndrome is a set of symptoms that a person may experience for weeks, months, or even years after a concussion or mTBI. Accurate diagnosis of mTBI, particularly for events in a combat setting, is particularly difficult. This is because the clinical terms used to define symptoms are commonly used in everyday language, and the diagnosis is often based on current post-concussion symptoms, which is often made retrospectively based on the patient’s self report, which can be extremely unreliable. Further complicating the diagnostic difficulties is the fact that, even with the best of intentions, there are biases and expectations on the part of both the clinician and the patient, complicated at times by potential secondary gain. These factors all conspire to lead to issues ranging across the spectrum from stoic denial to somatization to extreme over-endorsement of symptoms.
The fundamental issue in mTBI is neurocognitive impairment. If the individual genuinely has an mTBI then he or she will suffer from decreased processing speed, difficulty multi-tasking, poor cognitive endurance, difficulty setting goals or planning, and difficulty perceiving and correcting errors. This can lead to frustration, feeling overwhelmed with routine tasks, depression, and maladaptive behavior that may worsen symptoms. This can be problematic in a civilian involved in a discrete head injury event, but it can be even more complicated with a recent combat veteran. The recent military conflict has renewed a longstanding debate on whether post-concussion symptoms are caused by neurological or psychological factors.13 Despite the controversy, the patient and clinician need to acknowledge the possible head injury not only as a TBI but also as a psychologically traumatic event. It is unlikely that the symptoms and etiologies of mTBI and PTSD are easily defined separately, as a great deal of the manifestations of both disorders tend to overlap. A blast injury certainly fulfills the DSM-IV definition of an event that involved the threat of death, serious injury, and threat to physical integrity of self and others.4 Confusing the issue even further is the emergence of pseudobulbar affect (PBA) as a known possible sequelae of TBI, along with other neurological disorders. PBA presents with uncontrollable affective outbursts, typically laughing and/or crying without the accompanying emotion, or at least out of proportion with emotional context. It is possible that tearfulness could be attributed to lability associated with PTSD, so it is important to explore whether the patient feels emotion that goes along with the observed affect.14 This is a most important distinction to make, in that it opens a new therapeutic consideration. Dextromethorphan/quinidine (DMQ) has been recently approved by the Food and Drug Administration for the treatment of PBA, is typically well tolerated and, if observed affective dyscontrol is, in fact, attributable to PBA, may provide somewhat rapid relief.15
Experience with TBI in civilian populations has taught us that co-occurring psychiatric illness is common. In one study of 196 hospitalized adults with TBI, 13.9% had a depressive disorder and 9% had a panic disorder.16 PTSD also moderates the relationships of TBI and social/occupational dysfunction post-deployment.17 That is, without comorbid PTSD, mTBI has a much weaker association with poorer general health and greater healthcare utilization, compared to mTBI with comorbid PTSD.17 The tendency of many patients is to attribute any functional impairment to mTBI rather than to PTSD, which fosters a perception that recovery depends on neurologic factors and are out of the patient’s locus of control, which can lead to a more pessimistic attitude toward recovery. Patients also tend to avoid attributing symptoms to PTSD, owing to the valence of mental illness and stigma. Thus, when confronted with a patient with mTBI, clinicians must address the psychological component of their injury. Ongoing patient education and reassurance in this area is crucial.12
The typical patient with co-occurring PTSD and mTBI may have complex symptom presentation requiring multiple medication interventions to treat symptoms across various dimensions. Medical management is only one facet of the treatment of co-occurring TBI and psychiatric illness. The single most effective intervention in mTBI is education and reassurance over time.12 Optimal treatment will often require intervention by many other allied healthcare professionals to provide cognitive rehabilitation, behavioral training, psychotherapy, and other individualized therapeutic modalities. The psychiatrist must ensure that they are actively involved in this system and using it to support their therapeutic work.
PTSD manifests itself in a diverse collection of symptoms, which is compounded when co-occurring with mTBI. Ideally, the patient should be engaged in evidence-based psychotherapy in addition to using medications to control symptoms. A multi-disciplinary and collaborative approach is ideal for addressing the effects of multiple symptom clusters and enabling the patient to engage in psychotherapy. For the patient with PTSD and co-occurring TBI, the clinician must always consider how the medication regimen may affect neurocognitive function.
Clinicians have a wide variety of medications to choose from when approaching the patient with PTSD/TBI, although sertraline and paroxetine are the only pharmacologic agents that are formally approved for the treatment of PTSD. The effectiveness of these medications has been generalized to include other serotonin-specific reuptake inhibitors and other classes of antidepressants, but these are not the clinician’s only options for addressing specific symptoms of PTSD. PTSD symptoms are clustered into three diagnostic areas: re-experiencing, avoidance, and hyperarousal. Re-experiencing symptoms include intrusive recollections, nightmares, flashbacks, and significant distress at exposure to internal or external cues reminiscent of the traumatic event. Avoidant symptoms include actively avoiding thoughts, activities, or any other stimuli reminiscent of the event, as well as significant numbing of affect. Hyperarousal symptoms include insomnia, irritability, poor concentration, hypervigilance, and exaggerated startle.15 However, when deciding on a psychopharmacologic approach it may be more helpful to consider approaching the patient in terms of addressing symptom clusters of anxiety, affect, and re-experiencing in the context of PTSD, as well as overlapping comorbid mTBI.18
Psychopharmacological Treatment of Anxiety Symptoms
Anxiety symptoms of hyperarousal, hypervigilance, exaggerated startle, insomnia, and avoidant behavior are common in both PTSD and mTBI. These can be addressed effectively with sertraline19 or paroxetine.19 Paroxetine may be favored because of its mild hypnotic properties, which tends to make it more acutely anxiolytic. As an SSRI, however, its efficacy over the long term is likely to be equivalent to other drugs in this class. The mTBI patient may also find this agent to be overly sedating. When starting SSRI medications in any anxiety patient it is important to remember that some of these drugs can be acutely activating, which can appear to exacerbate anxiety. This effect can be mitigated by titrating the medication up slowly. Similarly, withdrawal effects, particularly notorious with paroxetine, can be mitigated by slowly titrating down when discontinuing SSRIs. Slow titration on initiating therapy or withdrawal will be especially important for the patient with co-occurring PTSD/mTBI so as not exaggerate or worsen associated cognitive difficulties. Indeed, even more care than usual may be warranted in patients presenting with co-occurring mTBI, as they often seem particularly sensitive to the effects of medications (as noted in the personal clinical experience of the authors).
Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, desvenlafaxine, and duloxetine19 are reasonable second-line options for anxiety symptoms in co-occurring PTSD/mTBI. The same considerations that apply to initiating or discontinuing SSRIs also apply to SNRIs. SNRIs are often found to be somewhat activating in the near term, so, once again, a slow titration may be in order. As with SSRIs, slow tapering can mitigate withdrawal effects, which are often observed after discontinuing SNRIs, venlafaxine in particular.
Duloxetine was studied recently in an open label trial including 21 patients suffering from treatment refractory (defined as having failed ≥2 trials of antidepressant medication) combat-related PTSD with comorbid MDD and was found to be beneficial for anxiety as well as depression symptoms in these patients. The study also reported that these patients experienced some improvements in nightmare symptoms,19 making duloxetine, and possibly SNRIs in general, particularly attractive in patients suffering from co-occurring PTSD and mTBI.
Tricyclic antidepressants can be quite effective in treating anxiety but should be used with caution in the patient with PTSD/mTBI because of the potential for anticholinergic side effects that may affect cognition. As a class, tricyclics are extremely dangerous in overdose and should be used with caution in patients who may be at risk for cognitive difficulties.
The anticonvulsant agents gabapentin and pregabalin19 have been found to be effective in treating both generalized anxiety and PTSD-related anxiety.20-24 Since secondary pain symptoms may occur in comorbid PTSD/mTBI, these medications, which have demonstrated efficacy in pain syndromes, may be considered when treating this comorbidity.25 Again, as with any of these medications, the clinician must exercise caution when using any of these medications and weigh the risks and benefits of possible effects of sedation on cognitive function with an individual with PTSD and mTBI. Note, however, that pregabalin may be as effective as alprazolam when treating insomnia in patients with anxiety, and it poses far less risk for amnesia and reduced cognitive function in this population.20-24
Benzodiazepines can be highly effective in treating anxiety symptoms, but this class of medications should be used with caution. No studies to date have demonstrated efficacy of these medications in PTSD, and co-occurring substance abuse/dependence considerations with PTSD are known to be a serious issue. The patient with anxiety symptoms and co-occurring mTBI may experience worsening of cognitive difficulties, concentration problems, memory problems, and behavioral disinhibition.
Psychopharmacological Treatment of Affective Symptoms
Affective symptoms in PTSD include irritability, detachment and numbing of affect, a sense of foreshortened future, and depressed mood. As with the anxiety symptoms, affective symptoms are most commonly addressed with sertraline or paroxetine. Other SSRIs are likely to be similarly efficacious. SNRIs are also reasonable alternatives. As noted earlier with regard to treating anxiety symptoms, TCAs should be employed cautiously given their propensity for eliciting anticholinergic side effects.
Again, the additional consideration in treating comorbid PTSD/mTBI is the effect that medication will have on the patient’s cognitive symptoms. If affective symptoms are refractory, the clinician may choose to augment an antidepressant with the dopamine partial agonist aripiprazole, or with low doses of quetiapine. Both are approved for adjunctive use in the treatment of MDD that fails to respond to an SSRI or SNRI.19
Aripiprazole was approved for augmentation of antidepressants in the treatment of MDD at low doses, generally in the 5–10 mg range. Aripiprazole has been started on open-label basis as monotherapy (average dosing being in the 10 mg range) for the treatment of PTSD with some encouraging results.26 Monoamine oxidase inhibitors are effective in treating depression, but should be used with caution in comorbid PTSD/mTBI. Maintaining the dietary restrictions necessitated by this class of drugs may be impractical and unwise in the context of cognitive difficulties.
Psychopharmacological Treatment of Re-experiencing Symptoms
One of the most vexing problems for the PTSD patient is that of re-experiencing the traumatic events. The patient experiences distress at reminders of the traumatic event; they have intrusive recollections, flashbacks, and, most commonly, nightmares about the traumatic experience. Nightmares can be extremely distressing, leading to a literal fear of going to sleep. When particularly vivid or extreme, this can worsen the initial trauma, and the resulting insomnia can severely impair therapeutic efforts. No formal indications exist, but some of the most promising data to date suggest that prazosin may be highly effective in controlling nightmares. Prazosin is a centrally acting alpha-adrenergic antagonist and may not only have a significant positive effect in reducing the frequency and intensity of nightmares but may also improve overall quality of sleep. Some studies even suggest an improvement in overall symptoms of PTSD.27-31
While there is no specific indication for treating nightmares with prazosin, and therefore no published dosing recommendations exist, available studies indicate that the effective dose lies somewhere between 5–15mg/day. As noted previously, clinicians should exercise caution, particularly in the patient with mTBI who may have difficulties with cognitive or neurological impairments, since the most prominent negative side effect will be hypotension and dizziness. It may be best in these cases to start at a minimum dose and carefully titrate up to a minimum of 5 mg as tolerated.
Trazodone and hydroxyzine are two other treatment options for nightmares and sleep difficulties. Trazodone, a serotonin reuptake inhibitor, is often used in low doses for its hypnotic properties.19 Hydroxyzine, a first-generation antihistamine with CNS depressant characteristics, is indicated both for sleep and anxiety, making it useful in PTSD not only in larger doses (50–150mg) for the initiation of sleep but also in smaller doses (25mg) on an as-needed basis throughout the day for anxiety.19
The non-benzodiazepine sedative hypnotics, including zolpidem, zaleplon, and eszopiclone,19 may be considered but should be used with caution. Sleep difficulties in PTSD are typically a long-term issue, and at least one study indicates that long-term use of benzodiazepines as a class is not particularly helpful in improving sleep quality.32 Since PTSD and mTBI are often comorbid with substance abuse/dependence, additional precautions should be applied. Sedative hypnotic drugs are often associated with a risk for amnesia,33 which can complicate an already difficult treatment course when combined with the cognitive and memory issues of a patient with mTBI. Although the desire for sleep is often the primary complaint, the clinician may find that methods of inducing sleep can leave the patient feeling out of control and amnestic, or worsen their cognitive impairment. Symptoms of hyperarousal and anxiety will be severely exacerbated if this occurs. Eszopiclone may have a slightly smaller risk for this.34 It has also been suggested that benzodiazepines, non-benzodiazepine hypnotics, antihistamines, and TCAs have possible negative effects on neural remodeling as a possible result of cholinergic side effects, further reducing the desirability of these agents in mTBI.35
Quetiapine is commonly used to treat nightmares and sleep disturbance. It is primarily a hypnotic drug in low doses (25–300mg range) and may also have some positive effect on the reduction of nightmare frequency and severity, secondary to alpha-adrenergic antagonist properties. It is important to keep in mind that quetiapine comes with significant metabolic risks that are not dose dependent, so the clinician must monitor the patient for weight gain, lipids, and glucose metabolism, just as when treating with high doses for bipolar disorder and schizophrenia.
Recent studies have shown that beta blockers have some potential in the secondary prevention of PTSD. Some studies indicate that beta blockers used within 6 hours following a traumatic event have resulted in some reduced symptomatology at 3-month follow-up.36 They may also be very useful in treating aggression, impulsivity, and acute anxiety, always keeping in mind the potential for cognitive impairment effects. While it has also been suggested that depression can be a side effect of beta blockers, other evidence counters that suggestion.37 Based on those same data, however, sexual dysfunction and fatigue are still significant possible side effects of beta blocker therapy.
Most importantly, keep in mind that the first-line treatment for sleep disturbance is behavioral. It is not uncommon to see delayed or advanced sleep phase and disturbances in overall sleep cycle in PTSD, TBI, affective disorders, anxiety disorders, and substance abuse/dependence disorders, all of which may be co-occurring to some degree in this patient population. And while there are limited data supporting the use of melatonin supplements or melatonin receptor agonists, such as ramelteon, for sleep disturbance in the context of TBI or PTSD,38 such options may be worth exploring, as the potential for abuse and cognitive disturbance is low with these agents.
The psychopharmacologic treatment of PTSD involves taking an approach from at least three different areas, encompassing anxiety, affective, and re-experiencing symptoms. Achieving any success with a single medication is unlikely, but a rational approach that considers the patient’s symptoms—including functioning and cognitive impairment if mTBI is involved—and addresses each of the above-noted areas with the symptom-based psychopharmacologic agent will likely produce the best result. In addition, when treating a patient with co-occurring mTBI, the clinician must involve other professionals in a multidisciplinary approach, always consider the neurocognitive effects of prescribed medications, and watch continuously for comorbidities of depression and substance abuse/dependence.PP
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