Sandeep Vaishnavi, MD, PhD

When the United States withdrew from Afghanistan earlier this year, clinicians noted a sharp increase in calls to veteran crisis center hotlines.

 One survey found that 90% of veterans with a history of mental illness were experiencing new or worsening symptoms since the country fell.

For veterans with posttraumatic stress disorder (PTSD), news about 

Afghanistan brought back powerful memories of traumas

 many of them were trying to forget. Nightmares invaded their sleep, intrusive thoughts distracted them from work and family, and flashbacks were so powerful there was no place to hide.

PTSD has a complicated history and neurobiology, and an array of potential comorbidities. In order to diagnose and treat it, clinicians should understand all these factors, and tailor their treatment plans accordingly.

The Prevalence of PTSD and Comorbid Disorders

Civil War General William Tecumseh Sherman put it bluntly when he said, “War is hell.” For veterans with PTSD, that hell can seem inescapable. Between the Iraq and Afghanistan wars, an estimated 500,000 US troops, about 20%, have been diagnosed with PTSD.

However, less than half of veterans in need of mental health services receive treatment. Of those who do get help, less than one-third receive evidence-based care.

 And of the 5 million service members being cared for by the US Department of Veterans Affairs (VA), only 8% have been diagnosed with PTSD. Left untreated, PTSD can lead to hospitalization, unemployment, and poverty.

There are myriad reasons for this lack of appropriate care. Veterans face unique barriers in getting treatment for 

. From the minute they enter the military, service members are trained to be tough. This, after all, is what gives them the mettle needed to survive. However, this attitude can also feed stigma, as any mental health condition might be considered a sign of weakness.

When the bullets stop flying and service members return home, the horrors they hoped to forget often follow. These unprocessed traumas bang on the door of their subconscious, demanding attention. However, talking about traumas can be an extremely uncomfortable experience, one that threatens to trigger retraumatization.

There are also societal barriers to access. Veterans who seek services from the VA must have received either an honorable or general discharge and, even then, there are usually long waits to receive services. Those living in rural areas are even less likely to get access.

Instead, many veterans turn to drugs and alcohol to dull the pain. In the 1980s, a study of Vietnam veterans with PTSD found that 74% had a comorbid substance use disorder (SUD).

 A more recent study found 76% met the criteria for both alcohol and SUDs.

Adding to the complexity, mood and anxiety 

 are high with PTSD and can complicate diagnosis and assessment. Veterans with PTSD are 3 to 5 times more likely to have major depressive disorder. Many also have anxiety disorders.

 wondering if they are irreparably broken. Between the wars in Afghanistan and Iraq, more than 30,000 veterans have died by suicide.

 It is a statistic that belies a troubling need for care.

PTSD has gone by many names over the years. During 

. During World War I, soldiers called it 

. After the Vietnam War, when almost 25% of soldiers required some kind of psychiatric care, it was known as 

The work of Charles Myers, MD, during World War I is widely credited with how PTSD is treated today. A medically trained psychologist, Myers was brought on by the British military to study and treat soldiers who were unable to function without any discernible cause.

At the time, many viewed shell shock as cowardice. Myers, on the other hand, argued that it was a psychiatric condition that caused affected soldiers to dissociate from a traumatic experience and repress its memory. The treatment, he concluded, involved connecting the traumatic memory back into one’s awareness through a series of psychotherapy sessions. These were ideally held within a military setting but away from gunfire.

 became an official diagnosis in the third edition of the DSM. Initially considered an anxiety disorder, PTSD is part of a separate group of trauma- and stressor-related disorders in DSM 5. DSM 5’s PTSD diagnosis also includes witnessing an event as a qualifying trauma.

PTSD is expressed by 4 main clusters of symptoms: reexperiencing the trauma in the form of intrusive memories, flashbacks, or nightmares; avoidance of anything that reminds an individual of the event; arousal and hyperreactivity, such as being easily startled or feeling tense; and effects on cognition and mood that include negative thoughts, feelings of guilt or blame, or a loss of interest. To receive a diagnosis of PTSD, these symptoms have to last more than a month and be functionally impairing.

Although anyone experiencing a trauma may have these reactions, symptoms usually fade over time and do not lead to PTSD. For others, however, the symptoms are severe, persist, and cause significant dysfunction.

The disorder can be diagnosed by using the Clinician-Administered PTSD Scale for DSM 5, a 30-item structured interview.

 It is considered the gold standard for measuring PTSD in clinical trials, but it is difficult to use in a clinic setting. The PTSD Checklist for DSM 5 is a 5- to 7-minute questionnaire that may be more practical to use in the clinic. It is regularly used to establish national PTSD outcome data.

Since the 9/11 terrorist attacks in 2001, 775,000 troops have 

 on a mission to retaliate and stabilize the region. More than 2400 died, about 20,000 were wounded, and countless others have been haunted by what they have seen and experienced.

When the Taliban regained control of Afghanistan in August, texts to the Veterans Crisis Line jumped 98% compared to a year prior. Chats and phone calls rose 40% and 7%, respectively.

 While this is troubling, the VA also noted it was an encouraging sign that more veterans were seeking help for their mental health issues. One survey revealed that one-third of veterans seeking counseling were doing so for the first time.

About 70% of veterans have struggled with mental health issues since serving in the Afghanistan war.

 Since August, 90% of Afghanistan service members have experienced new or worsening mental health issues. About 75% are experiencing new or worsening symptoms of depression, 58% have started or increased drug or alcohol use, and 64% have new or worsening thoughts of suicide.

 tend to experience more severe symptoms and lower remission rates compared to noncombat-related PTSD.

 Indeed, the kind of warfare experienced in Afghanistan is likely to put anyone on edge. This includes guerrilla attacks, roadside and suicide explosives, and a wary uncertainty about safe zones and battlegrounds. When an attack can come from anywhere at any time, the amygdala will be more active, and PTSD may be more likely.

Although improvements in body armor and combat medicine protect service members who would have died from their wounds in earlier wars, it leaves them with psychological scars as well as possible PTSD, brain injury, and a host of other lifelong debilities.

Troops today are serving at younger, more impressionable ages.

 In the Vietnam War, troops mostly served a single tour. Now, more than half return to action, with some serving more than 5 tours.

 Studies have shown that morale decreased and psychiatric problems as well as the use of psychotropic medication increased during the second or third deployment. Similarly, communication with family was difficult, and separation or divorce rates increased.

Younger age, female gender, minority background, as well as lower socioeconomic status, military rank, and education all indicate a higher risk of PTSD.

 In addition to trauma from battle, sexual trauma is common in the military, with about 1 in 3 women and 1 in 50 men reporting military sexual trauma (MST).

 With fewer women in the military, 1 in 3 veterans who report MST are men.

In addition to PTSD, many Afghanistan combat veterans also suffer from moral injuries, which occur when a trauma cuts so deep it violates an individual’s moral beliefs.

 Moral injury also describes an individual’s internal conflict over things they have done to others, actions they have failed to do, and events they have witnessed others doing or failing to do. Examples of moral injury include killing others (innocent or not), dismembering bodies, torturing others, or abandoning comrades during battle.

Moral injury is highly common among service members, with at least 1 symptom appearing in 90% of veterans and 80% of active duty military.

 It is a separate and distinct syndrome from PTSD that can co-occur and be influenced by the same event. Although it shares similar symptoms with PTSD, it would be a mistake to treat it the same. In fact, the existence of unresolved moral injury can hinder the treatment of PTSD, as well as 

Shame is the underlying theme of moral injury. It is shaped by the event that caused it, and it continues to develop for years after a service member has returned home.

 Disgust also plays a major role. Studies indicate that elevated levels of disgust, whether moral or bodily, can increase intrusive thoughts and tend to be higher in those with PTSD.

Moral injury also involves feelings of guilt, betrayal, loss of meaning and trust, difficulty forgiving, self-condemnation, and inner conflict over moral implications. Moral injury can shake a patient’s spirituality and call into question their relationship with a higher power.

 It is also correlated with social anxiety isolation, depression, and 

As the understanding of PTSD has advanced, it has become clear that it is a neurobiological disorder driven by environmental trauma. It is likely a product of both nature and nurture and may be caused by a combination of biological vulnerability and 

PTSD involves the amygdala, prefrontal cortex, and hippocampus. The amygdala regulates intense emotions, particularly fear. It governs fear conditioning and contributes to symptoms of altered arousal and reactivity. The prefrontal cortex regulates conditioned fear, normally turning down the alarm signal from the amygdala. PTSD can occur when decreased activity in the prefrontal cortex prevents it from appropriately regulating heightened activity in the amygdala.

The hippocampus can help buffer the effects of increased amygdala activity. There is evidence to suggest that the hippocampus tends to be smaller in those with PTSD, but it is not entirely clear whether that is the cause of PTSD or the result of it. Studies of identical twins have indicated that a smaller hippocampus at baseline may make people more vulnerable to developing PTSD.

Since the fall of Afghanistan, 31% of veterans have sought professional mental health services for the first time.

 It is a sign of hope that barriers to treatment are softening. 

, in particular, has become a useful way to reach patients who are either hesitant to engage in treatment or live in remote places.

A 2014 survey of 7600 veterans revealed that those who believed they needed treatment, kept a positive attitude, and had strong social networks were more likely to be successfully treated for PTSD.

 However, treating PTSD can be a challenge, and current treatment options are not always effective.

Close to 60% of those with PTSD do not achieve remission, and although treatment-resistant PTSD is hard to define, up to one-third of patients do not find relief with current therapies.

 Chronic PTSD can lead to decreased life satisfaction as well as increase suicide risk and depression rates.

Trauma-informed care seeks to tailor treatment around the unique vulnerabilities of each patient. The goal is to help a patient process their PTSD experiences without retraumatizing them in the process. To do this, clinicians need to fully understand every aspect of a patient’s traumatic event, including earlier ones. Additionally, they put a high emphasis on safety, encourage patients to rebuild control, and teach them to build upon their individual strengths.

Homeless veterans with PTSD, in particular, can benefit from trauma-informed care. While veterans comprise 7% of the total US population, they represent 12% of homeless adults.

Providing a trauma-informed approach necessitates adapting treatment to the needs of these patients. It helps earn their trust and protects them from retraumatization. PTSD is like a giant wound that many veterans will carry throughout their lives. Healing must start from the inside out. As clinicians, our job is to help them integrate the experience of trauma without being overwhelmed by it.

 used as first-line treatments of PTSD. With cognitive processing therapy, therapists teach patients coping skills and help them identify negative thoughts associated with a traumatic event and replace those thoughts with coping skills. With prolonged exposure (PE), patients revisit the trauma repeatedly in a safe, clinical setting to change how they react to the memories of the event. PE has an efficacy rate of about 60% of veterans with PTSD.

. In treating PTSD, the use of medications, specifically selective serotonin reuptake inhibitors (SSRIs), is to make therapy more effective by reducing the intensity of the overwhelming anxiety caused by PTSD. This anxiety can limit how effectively patients are able to discuss and process their trauma in therapy, which can hinder the healing process. SSRIs have a 60% rate of response in patients with PTSD, but only 20% to 30% achieve complete remission.

, such as ketamine and psilocybin mushrooms, is also currently being researched in their potential to treat PTSD, but these studies are still in the early stages of understanding how they might be useful.

Eye-movement desensitization reprocessing (EMDR).

 After ensuring a patient is prepared to process their trauma, this treatment works to replace negative images and beliefs with more positive ones. During treatment, a patient pays attention to a back-and-forth sound or movement while recalling a traumatic event. The sound or movement gives them a focus that allows them to explore and process their trauma.

 is showing potential as a possible future treatment. It works by delivering highly focused magnetic fields to modulate neural circuits in the brain. It is currently used for patients with treatment-resistant depression. Studies indicate TMS could be used to treat the poor extinction of traumatic memory by targeting the prefrontal cortex.

. Yoga and breathing-based meditation are thought to help calm the hyperactive sympathetic nervous system brought on by PTSD. In one study, veterans who practiced Sudarshan Kriya yoga showed reductions in PTSD scores, anxiety symptoms, and respiration rate.

 In another study, half of the group of veterans who practiced transcendental meditation for 3 months did not meet the criteria for PTSD at study completion, compared to a control group at 10%.

 has also been shown to indirectly reduce self-stigma felt by many veterans as well as other symptoms of PTSD.

. For veterans suffering from moral injury, programs such as 

 can help trauma survivors address a variety of spiritual concerns.

In these programs, which are administered by trained chaplains, veterans explore issues of forgiveness, their relationship with a higher power, and why that higher power allows evil to occur in the world.

 is still under investigation, it seems to have a positive effect on those with PTSD. One study found that cannabis lowered threat-related activity in the amygdala.

 A second study observed that cannabis seemed to diminish the intensity of memories associated with trauma.

 The use of cannabis to treat PTSD has not been approved by the US Food and Drug Administration and remains illegal in many states.

Articles

The US withdrawal from Afghanistan stirs memories of trauma among veterans.

PTSD’s Long Reach

Traumatic brain injury (TBI) is a public health epidemic. Approximately 2.8 million people sustain a TBI annually; of these, approximately 50,000 die, 282,000 are hospitalized, and 2.5 million are discharged from an emergency department.

 Mild TBI or concussion accounts for the majority of TBIs. Falls are the most common cause of TBI, followed by assault and motor vehicle accidents. According to recent statistics, during a 6-year period from 2007 to 2013, rates of TBI-related ER visits increased by 47%, but rates of hospitalization and death decreased by 2.5% and 5% respectively, underscoring the importance of managing TBI morbidity.

Psychiatric disturbances are the most common long-term sequelae of TBI. In a recent article on the epidemiology and natural history of psychiatric disorders after TBI, Ponsford and colleagues

 noted that compared with the general population, patients with TBI have increased incidence of depressive disorder, anxiety disorder, and PTSD; depressive disorders are likely to be chronic and persistent.

In this article, we define TBI psychiatric disturbances as the development of psychiatric symptoms (emotional, behavioral, or cognitive) after the occurrence of a single or multiple TBIs. It may not always be possible to establish a causative link between TBI and the onset of psychiatric problems. When not possible, TBI should be considered as a treatment-informing medical comorbidity rather than an etiological factor.

Appropriate management of psychiatric disturbances can result in better outcomes, improved quality of life, and decreased societal impact. Management of TBI psychiatric disturbances should always be multidisciplinary and include both pharmacological and non-pharmacological interventions. An extensive armamentarium of pharmacological options is available, and there have been a number of randomized controlled trials and meta-analyses (

 TBI-associated depression is characterized by prolonged, persistent sadness associated with other symptoms such as anhedonia, lack of motivation, decreased self-care, variable sleep and/or appetite pattern, feelings of hopelessness, and/or suicidal thoughts. These symptoms may last for a couple of weeks to months (major depressive episode) or persist in a milder form for two or more years (dysthymia).

SSRIs are often considered first-line agents because of their benign side effect profile. Sertraline, citalopram, and escitalopram are often favored because of their limited drug-drug interaction. Most clinical trials have focused on sertraline, but results have been inconsistent. In a trial comprising 15 patients with mild TBI 87% had a significant response and 67% achieved remission with sertraline.

 In a follow-up study of patients with TBI-associated depression no significant differences were seen between sertraline and placebo in depression severity, response, or remission rates.

 found no statistically significant difference between sertraline and placebo in a group of 52 patients with TBI-associated depression. However, the small sample size (N=11) and the high rate of discontinuations may have contributed to the lack of difference between the medication and placebo groups.

SNRIs have also been used with fair success and no significant adverse effects, but they have not been systematically studied. In a small study (N=10) the tricyclic antidepressant (TCA) desipramine was shown to reduce depressive symptoms.

 However, because of anticholin- ergic adverse effects and risk for seizures, TCAs are less favored. Nortriptyline is considered to be the least anticholinergic and antihistaminergic among the TCAs and has demonstrated efficacy in the treatment of depression following stroke.

 However, we are not aware of controlled trials of nortriptyline in the treatment of TBI depression.

Monoamine oxidase inhibitors (MAOIs) may also be considered in persons with recalcitrant depression. However, the need for dietary restriction can be challenging because adherence to a strict diet may be difficult for patients with TBI who have cognitive deficits.

 conducted a systematic review and meta-analysis to determine the effectiveness of pharmacotherapy for the treatment of TBI depression and found a large, favorable treatment effect (Hedges g = 1.169; 95% CI, 0.849-1.489; 

<.001) on pooled analysis of within-groups treatment effect. Even when the analysis focused on only placebo-controlled trials, treatment with antidepressants was associated with a statistically significant reduction in depressive symptoms.

Methylphenidate and other stimulants may be used to augment the effect of antidepressants, especially when there is evidence of fatigue, apathy, or executive function deficits. Lee and colleagues

 compared the efficacy of sertraline, methylphenidate, and placebo in a study of 30 patients with mild to moderate TBI. Both methylphenidate and sertraline significantly improved symptoms of depression, but only methylphenidate improved cognitive function. Patients treated with methylphenidate also had diminution in daytime sleepiness.

Electroconvulsive therapy (ECT) may be safe and effective in patients with TBI. Jorge and Arciniegas

 have suggested some common-sense approaches to using ECT in patients with TBI: use low energy levels to generate a seizure of about 20 seconds, use pulsatile currents, increase between-treatment time intervals to 2 to 5 days, and keep the number of treatments to a minimum. Non-dominant unilateral ECT has a decreased risk of cognitive adverse effects compared to bilateral ECT and may be preferable in TBI patients.

 In a review of 48 studies, Simpson and Tate

 concluded that the risk of suicide, suicide attempts, and suicidal ideation is increased in TBI survivors compared with the general population, even after adjusting for psychiatric comorbidities. Mackelprang and colleagues

 also noted that 25% of their sample of 560 patients with all severities of TBI reported suicidal ideation during the first year following a TBI, a number much higher than 3.7% reported for the general population.

As in other cases of suicidal ideation, the most important factor in the management of TBI-associated suicide is to maintain safety. Immediate hospitalization should be considered for patients with active suicidal thoughts with intent or plan to die. Management of suicidal thoughts associated with psychiatric disturbances after TBI should focus on the psychiatric disturbances themselves. Extra caution to maximize safety is needed not only in the inpatient setting but also in the outpatient setting, ensuring that the patient has consistent outpatient care and a strong supportive network.

 The incidence of bipolar spectrum disorders is low in the TBI population, with a range of 2% to 9% in the first year after injury.

 Findings indicate the estimated lifetime relative risk for bipolar and related disorders to be 1.1, similar to the lifetime risk of bipolar disorders in the general population.

TBI mania is characterized by changes in mood, sleep, and activation, which may manifest as irritability, euphoria, insomnia, agitation, aggression, impulsivity, or even violent behavior. There is scant literature on the pharmacological management of TBI mania.

Based on our clinical experience and case reports, we recommend use of quetiapine as a first-line and risperidone as a second-line agent for acute mania; we recommend valproate as first-line and carbamazepine as a second-line agent for maintenance. Although many psychopharmocologists might argue that lithium is the gold standard for the treatment of idiopathic bipolar disorder, we are concerned about the CNS and motor adverse effects in persons with TBI.

 A wide range of anxiety disorders may occur after TBI including generalized anxiety disorder, agoraphobia, social phobia, panic disorder, and obsessive-compulsive disorder. Results from a meta-analysis of the prevalence of generalized anxiety disorder and self-reported anxiety in adults with non-penetrating TBI showed that 11% had a diagnosis of GAD, and 37% reported clinically significant levels of anxiety.

Commonly used medications for treatment of anxiety include sertraline, escitalopram, citalopram, and venlafaxine at doses similar to the treatment of TBI-associated depression.

. In a study of 1084 patients with mild TBI, 13% of the patients had PTSD.

 Higher incidence has been seen in military studies. Carlson and colleagues

 found that 64% of 836 veterans from Iraq/Afghanistan had PTSD. A recent review confirmed that PTSD occurs after TBI, but is more common after mild TBI.

 Although rates of TBI vary in the civilian population, they are higher in the military population, and the risk increases with the severity of TBI. The researchers concluded that the risk of PTSD varies according to the context in which the TBI occurred, the psychological trauma experienced at the time of TBI, and pre-TBI history of trauma or PTSD.

Sertraline is the first-line option for treating comorbid PTSD and TBI. Citalopram is a second choice, but caution is recommended above 40 mg daily because of potential cardiac adverse effects. Second-line agents include fluoxetine and mirtazapine, although the latter may be associated with mild anticholinergic adverse effects. SNRI antidepressants can also be used safely. Tricyclic antidepressants are third-line options. Prazosin may be used as adjunctive treatment for persistent nightmares. However, there were no statistically significant differences in sleep quality between prazosin and placebo in a recent 10-week study.

Extreme caution should be used with benzodiazepines for treatment of anxiety disorders or PTSD. In general they should not prescribed for more than 2 weeks because longer use increases risk for dependence. TBI patients may have increased susceptibility to the adverse effects of benzodiazepines, including drowsiness, ataxia, slurred speech, memory impairment, psychomotor impairment, and possibly disinhibition. Moreover, benzodiazepines may aggravate the fear response in persons with PTSD.

. Psychotic symptoms are not uncommon after TBI. There are predominantly 2 types of TBI-related psychosis: delusional disorders and schizophrenia-like psychosis. As far as we know, there are no clinical medication trials on the management of TBI psychosis. Case reports suggest efficacy for second-generation antipsychotics.

 Based on our clinical experience, we recommend second-generation antipsychotics (risperidone, 0.25-4 mg; quetiapine, 25-200 mg; lurasidone, 20-80 mg) over first-generation antipsychotics because the latter may interfere with neural recovery in TBI. When there are concerns about the presence of seizures, anticonvulsants such as valproate or carbamazepine may be preferable.

. Apathy refers to a syndrome of disinterest, disengagement, inertia, lack of motivation, and absence of emotional responsivity. Although there are also emotional and cognitive aspects of apathy, we have chosen to include apathy under behavioral disturbance, as the disengagement and lack of involvement is most distressing for caregivers. Apathy can be a symptom of depression, which is the most common presentation, or occur as an isolated syndrome. As with most psychiatric disturbances in TBI, only reviews, anecdotal reports, and small case series are available to guide management. Most of the literature favors methylphenidate. Based on this and on our clinical experience, we recommend methylphenidate as a first-line agent.

. Sleep disturbances are common after TBI and can occur in isolation or as a symptom of a psychiatric disorder. Insomnia is the most common sleep disturbance, seen in about 50% of patients with TBI, although other disturbances such as hypersomnia, sleep apnea, and sleepwalking may also be present. Treatment of TBI sleep disturbance varies according to the type of sleep disorder and related comorbidities. Comprehensive medical evaluation including an overnight sleep study can help with the diagnosis of sleep disturbance. Maintenance of sleep hygiene is always first in the management of sleep disturbances. When sleep disturbance is comorbid with a psychiatric disorder, it is important to treat the underlying psychiatric disorder.

When insomnia occurs in isolation, consider use of a non-benzodiazepine hypnotic such as zolpidem for a short period. Other agents such as melatonin, amitriptyline, lorazepam, and zopiclone may also be considered. Benzodiazepines should be avoided secondary to risk for addiction, motor and cognitive adverse effects, and paradoxical rage outbursts. In patients with TBI who have excessive daytime sleepiness, sleep apnea should first be ruled out. Modafinil (100-400 mg) or armodafinil (150-300 mg) can be considered in patients with persistent and unexplainable daytime sleepiness.

. Other common behavior disturbances include impulsivity, aggression, and disinhibition. As with other psychiatric disturbances, management of post-TBI behavior problems should always be multifaceted. This includes a combination of environmental modification strategies, behavioral therapy, supportive therapy, family therapy, and pharmacotherapy. Medications should be based on presence of comorbid neuropsychiatric disturbances.

The constellation of cognitive impairments following TBI is variable and depends on the severity of the location of the injury on the brain. TBI can affect every cognitive domain, including attention, memory, visual-spatial processing, language, social cognition, and executive functioning.

The core intervention for cognitive impairments is cognitive rehabilitation, which includes use of remediation techniques and external strategies to help individuals compensate for the deficits. In addition to cognitive rehabilitation, there are some pharmacologic options for augmenting cognitive functioning. The three main classes of pharmacological agents utilized to treat the cognitive sequelae of TBI are psychostimulants, cholinergics, and NMDA receptor antagonists.

. Psychostimulant medications are commonly used to improve arousal/attention and related neurobehavioral symptoms after TBI. Methylphenidate is the first-line agent and most commonly used (5-40 mg/d). Methylphenidate may improve arousal, attention, and processing speed and general cognitive function in the subacute and chronic phase of injury. Lee and colleagues

 have also noted improvement in cognitive function and reduction in daytime sleepiness in addition to improvement in depression in persons with depression following TBI.

. Donepezil and rivastigmine have been studied for cholinergic augmentation following TBI. Donepezil is a centrally selective acetylcholinesterase inhibitor that has been may improve attention and memory during the subacute and chronic phase of injury and enhance sensory gating during the chronic TBI period. Rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase improved scores on the Hopkins Verbal Learning Test and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing mean latency, but only in patients with severe memory impairment at baseline.

-methyl-D-aspartate (NMDA) receptor antagonists

. Amantadine and memantine are non-competitive antagonists at the NMDA receptor. They also enhance dopamine release, decrease presynaptic dopamine reuptake, stimulate dopamine receptors, and enhance postsynaptic dopamine receptor sensitivity. Amantadine was noted to help with arousal in the acute TBI period and with attention, visuospatial function, and executive functions in chronic TBI in persons with moderate to severe TBI.

 In our clinical experience, amantadine at dosages of 100-400 mg daily may be helpful for the treatment of executive dysfunction, more specifically for impulsivity, disinhibition, and poor motivation.

As far as we know, the efficacy of memantine on the psychiatric sequelae of TBI has not been studied. However, a recent prospective randomized trial in patients with moderate TBI revealed that patients in the memantine group compared with placebo had significantly reduced serum neuron-specific enolase levels by day 7 of injury, and improved Glasgow Coma Scale scores on day 3 of the study, underscoring its neuroprotective effect.

Another approach is to use cognitive brain training. There are ongoing studies to see if intensive cognitive games can help in TBI. Elbogen and colleagues

 have studied a mobile cognitive training app (CALM) in TBI; they found that emotional regulation improved; however, executive functioning did not.

Psychiatric symptoms after TBI are common and troublesome. As TBI rates continue to remain high, there are many patients with long-term sequelae such as mood, behavioral, or cognitive symptoms.

Treatment of TBI symptoms is in line with treatment of symptoms in idiopathic psychiatric disorders; however, dosing may vary because of the potentially heightened sensitivity of the traumatized brain. There are also some medications used in TBI patients that are not used very often in general psychiatry, such as amantadine. (See 

 for a summary of suggested agents to use in TBI.)

Unfortunately, there are limited studies for psychiatric symptoms after TBI; thus, there is a need for randomized, controlled trials. Hopefully, future treatment will be based on more rigorous group data but also with more personalized recommendations (based on biomarker or pharmacogenetic testing results). Optimal treatment may involve multimodal approaches, with pharmacotherapy, behavioral therapy, cognitive brain training, and neuromodulation.

Dr Rao is Associate Professor, Department of Psychiatry and Behavioral Sciences and a member of the Miller Coulson Academy of Clinical Excellence, Johns Hopkins University, Baltimore, MD; Dr Vaishnavi is a Neuropsychiatrist, The Preston Robert Tisch Brain Tumor Center, Duke University. He is on the Faculty of Duke Institute for Brain Sciences, and Director, Transcranial Magnetic Stimulation and Director, Clinical Trials Carolina Partners, Durham, NC.

The authors report no conflicts of interest concerning the subject matter of this article.

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Traumatic brain injury (TBI) is a public health epidemic. Psychiatric symptoms after TBI are not just common, but also troublesome.

Pharmacological Management of the Psychiatric Aspects of Traumatic Brain Injury

Traumatic brain injury (TBI) is best defined as an alteration in brain functioning or brain pathology caused by an external force. The rapid acceleration or deceleration external forces can be caused by blunt trauma, penetrating objects, or blast waves. The resulting primary damage includes shearing/tearing injuries of white matter, focal contusions, hematomas, or cerebral edema. Soon after the primary damage, a cascade of metabolic events sets in, which can cause secondary brain damage that may result from the generation of free radicals, release of neurotransmitters, inflammatory responses, calcium-mediated damage, mitochondrial dysfunction, and gene activation. TBI is associated with both focal and diffuse neuronal damage at the site of impact and in more distant brain regions.

TBI is classified as mild, moderate, or severe using the Glasgow Coma Scale (mild, 13 to 15; moderate, 9 to 12; severe, 8 or less); by the duration of loss of consciousness (mild, 30 minutes or less; moderate, 30 minutes to 24 hours; severe, more than 24 hours); or by the duration of posttraumatic amnesia (mild, 1 hour or less; moderate, 1 to 24 hours; severe, 1 to 7 days; and very severe, more than 1 week).

Sleep-related problems are among the most disabling consequences of TBI, with multiple influences: impairment of neuronal plasticity, metabolomic alterations, loss of vascular homeostasis, and disruption of the blood-brain barrier. Moreover, patients with TBI sleep disturbances are more sensitive to pain; are at greater risk for neuropsychiatric problems, such as depression and anxiety; perform poorly on neuropsychological tests of memory, attention, and executive function; and have worse social functioning.

 They have longer hospitalization stays and once discharged from the hospital are at increased risk for suicide.

Sleep disturbances can occur during both the acute and chronic phases of injury. Acute posttrauma phase sleep problems have the potential to interfere with neuronal recovery that may be complicated further by treatment with medications, such as benzodiazepines and haloperidol, which can be detrimental to the recovering nervous system. In the subacute and chronic phases, daytime drowsiness can impair participation in rehabilitation while nighttime wakefulness is often associated with psychiatric problems, behavioral dyscontrol syndromes, and overall poorer quality of life.

Patients with all severities of TBI are at risk for sleep problems, although some studies have noted increased rates with mild compared with severe TBI.

 However, these findings may be due to a lack of awareness or underreporting in persons with severe TBI, or perhaps because of the increased sensitivity to changes after mild TBI. Some findings suggest that there are changes in polysomnographic measures following TBI, such as longer sleep onset latencies, shorter REM onset latencies, frequent nighttime awakenings, and higher proportion of stage 1 sleep.

The sleep-wake cycle depends on the coordinated function of multiple brain regions, including the brain stem, basal forebrain, hypothalamus, and the frontal-subcortical system, as well as a balance between the arousal activating and inhibitory systems (Figure). CT and other structural imaging devices can miss sleep-associated microstructural abnormalities in the brain. For example, in one study, CT scans did not pick up any brain damage, but when polysomnography was done, significant differences in electroencephalogram power spectra data were seen.

The causes of sleep disturbances after TBI are not well understood. However, the mechanisms underlying sleep-wake cycle problems may include the disruption of neural circuits as well as a myriad of other medical and psychiatric disturbances and environmental factors.

Individuals who have experienced TBI, even with mild severity, frequently complain of ongoing sleep disruption and excessive daytime sleepiness. A comprehensive evaluation of sleep-related symptoms may reveal various comorbid sleep disorders, including the following DSM-5 diagnoses (

• Insomnia disorder: roughly one-third of adults in the general population have occasional insomnia and about 6% to 10% meet the criteria for insomnia disorder; approximately 30% to 50% of patients who have suffered a TBI experience insomnia.

• Hypersomnolence disorder: hypersomnolence affects about 20% of patients during the chronic post-TBI period.

• Narcolepsy: the prevalence of narcolepsy in the general population is 0.02% to 0.04%; the estimated prevalence in patients with a TBI is 3% to 5%.

• Breathing-related sleep disorders: obstructive sleep apnea hypopnea is present in 2% to 15% of middle-aged adults; among TBI patients, the prevalence is 23% to 36%.

• Circadian rhythm sleep-wake disorders: the prevalence of these disorders in the general population is relatively low, although adolescents and young adults are more likely to have a delayed sleep phase while older adults are more likely to have an advanced pattern.

• Restless legs syndrome: approximately 2% to 7% of individuals in the general population have symptoms of restless legs syndrome; among TBI patients, the reported rate for periodic limb movements in sleep is around 17%

; for restless legs syndrome, the rate is 13%.

• Parasomnias: the prevalence of many parasomnias in both the general and the TBI population is unclear. Bjorvatn and colleagues

 report a lifetime prevalence of 4% to 67% in the general population, with sleep talking and nightmares accounting for 67% and sleep-related injuries and eating accounting for about 4%; Verma and colleagues

 report a rate of 25% in the TBI population, with REM behavior disorder being the most common.

Evaluation of sleep disturbances after TBI

When evaluating a brain-injured individual with sleep disturbances, a comprehensive evaluation is needed to rule out general medical conditions, psychiatric disturbances, and environmental factors 

). The key elements are a detailed history from the patient and collateral information from his or her family, a review of medical records, and the use of problem-focused laboratory tests.

When evaluating general medical problems, a systems-based approach is needed because endocrine, cardiac, respiratory, neurological, and musculoskeletal factors can contribute to or precipitate sleep disturbances following TBI.

In the formulation of TBI sleep disturbances, bear in mind injury-related factors (eg, nature and severity of injury, location of injury), pre-injury factors (eg, medical and psychiatric problems, substance abuse), and post- injury factors (eg, medical and psychiatric problems, substance abuse, cognitive and personality changes associated with the injury, injury- related psychosocial stressors).

We advocate the 4 perspectives of the psychiatry model developed by McHugh and Slavney18 that serves as a “toolbox” to formulate and treat TBI sleep disturbances. This approach includes the disease perspective that focuses on the broken part in the brain and includes injury- and non–injury-related biological factors; the dimensional perspective that considers premorbid and/or injury-related cognitive and personality vulnerabilities; the behavior perspective that examines abnormal goal-directed behaviors; and the life story perspective that captures pre- and post-injury psychosocial stressors (

If sleep disturbances persist after optimizing the management of general medical and psychiatric conditions, more thorough sleep assessments should be considered. These may include subjective assessments, such as a review of sleep diaries and standardized sleep scales (eg, Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale), to determine the severity and the character of the disturbances.

The key elements of a sleep diary include:

• Amount of alcohol and caffeine consumed and time of consumption

• Medications taken before going to sleep

Referral to a sleep clinic for overnight polysomnographic testing also may be helpful. Polysomnographic testing can be useful to determine sleep architecture alterations and to diagnose upper airway resistance syndrome, obstructive and central sleep apnea, nocturnal seizures, parasomnias, and periodic limb movements.

While polysomnographs are the gold standard for objectively measuring sleep disorders, patients may be unwilling to have overnight sleep studies or it may not be possible to refer them to sleep clinics. In these situations, home sleep testing with type III devices is a practical alternative, especially when there is high suspicion of obstructive sleep apnea.

For patients who are unwilling or unable to have overnight sleep studies, actigraphy may be a good alternative. Actigraphs are small, wristwatch-size accelerometers that are worn on a limb and record data on patient movement continuously for several days. These devices differentiate between sleep and waking based on the amount and pattern of body movement. Actigraphy is especially valuable because of ease of its use and extended recording.

Establishing a diagnosis is crucial. Before initiating medications for sleep, the focus is on the treatment of medical and psychiatric comorbidities. Nonpharmacological strategies such as sleep hygiene (

Sleep-related problems are among the most disabling consequences of TBI, with multiple influences: impairment of neuronal plasticity, metabolomic alterations, loss of vascular homeostasis, and disruption of the blood-brain barrier. The authors take a close look.

Sandeep Vaishnavi, MD, PhD

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