Acute Stress Disorder

Etiology

According to the survey-based studies, twenty to ninety percent of the general population is exposed to one or more extreme stressful events in their life.[6] Although a large number is exposed, only 1.3 to 11.2 percent of acute stress disorder (ASD) developed long-term symptomatic disease (such as PTSD).

Risk Factors

There is limited evidence on risk factors for developing ASD after a traumatic event. However, the risk factors for PTSD could also be applied to ASD due to its close resemblance. Based on the two metanalyses performed by Ozer et al. and Brewin et al., Sareen J. categorized risk factors in three buckets:[7][8][9]

1. Pretrauma factors: 
   1. Female gender
   2. Intellectual disability
   3. Lack of education
   4. History of traumatic events
   5. History of psychiatric disorder(s)
   6. Personality disorder(s)
   7. Genetics
2. Peritrauma factors:
   1. Trauma severity
   2. Assault
   3. Rape
   4. Physical injury
3. Posttrauma factors:
   1. Acute stress disorder (ASD)
   2. Tachycardia
   3. Poor socioeconomic status
   4. Physical pain severity
   5. ICU stay
   6. Brain injury
   7. Dissociative symptoms
   8. Disability
   9. Subsequent life stress

Epidemiology

Acute stress disorder (ASD) was initially added to the DSM-IV 20 years ago, but there is limited data on its prevalence, especially in the general population. While ASD is a separate diagnosis compared to PTSD, but the difference is limited to the duration of ASR symptoms, making ASD prevalence measurement more complicated. ASD prevalence is highly variable based on the study and nature of the trauma. The prevalence rates of ASD were reported less than one week post-injury at 24.0 to 24.6% and 1 to 2 weeks post-injury at 11.7% to 40.6%.[10]

Furthermore, there have been some epidemiologic studies on specific populations. A meta-analysis performed by Wenjie Dai et al. in 2018 on the prevalence of ASD among road traffic accidents showed a pooled prevalence of 15.81% (95% CI: 8.27-25.14%). Thirteen studies in eight countries pooled a total of 2989 accident patients. The results show the significance of early ASR symptoms in surveillance and therapy.[5] ASD prevalence in emergency room encounters among children (7 to 17 years) exposed to trauma was 14.2 in two weeks. The prevalence of PTSD at nine weeks was 9.6 percent.[11] In the postpartum cross-sectional study, mothers having preterm babies had significantly higher ASD than term babies ( 14.9 % versus 0%, 95% CI: 2.16;617.61, OR: 36.5).[12]

Pathophysiology

The exact reason why most people recover after a traumatic event but few develop acute stress disorder (ASD) remains unknown. Various models were developed to explain the response to traumatic events. The majority of them are related to "fear conditioning." It is a form of Pavlovian learning that when a traumatic stimulus (e.g., explosion) occurs together with a neutral stimulus (e.g., smell) or context (e.g., night time), in the future encounters of the neutral stimulus or context, the brain, and the body exhibits the same fear responses (even in the absence of the traumatic stimulus).[13]

Most healthy people adapt to fear conditioning by extinction learning - a gradual reduction in response to the traumatic stimulus. If this mechanism fails, the patient continues to re-experience fearful symptoms of the initial traumatic event.[2]

Functional magnetic resonance imaging (fMRI) scans of PTSD patients have shown hypoactivity of the frontal cortex and hyperactivity of the temporal cortex, demonstrating the possibility of a correlation between PTSD and neural functioning.[14] A more recent study showed hyperactivation of the superior prefrontal and cingulate cortex and medial posterior precuneus.[15]

History and Physical

The American psychiatric association, DSM-5 defines acute stress disorder (ASD) criteria as the followings:[16][17]

• A: Being exposed to a traumatic event (either physically, sexually, or mentally) plus
• B: Having more than eight of the following symptoms (clustered in five categories) plus:
  1. Intrusion symptoms: 
     • Distressing memories of the traumatic event are recurrent. Children may have repetitive game plays in themes mimicking the main event.
     • Having repetitive dreams related to the traumatic event. In children, it might be in the form of night terrors.
     • Enactment of the traumatic event recurrence (i.e., flashbacks).
     • Intense or prolonged mental or physicological distress in response to the events or themes reminding the patient of the actual traumatic event.
  2. Negative mood:
     • Inability to be happy, feel successful or feel love.
  3. Dissociative symptoms:
     • Having a sense of being detached from self and emotions.
     • Dissociative amnesia (that is not related to intoxication or traumatic brain injury [TBI])
  4. Avoidance symptoms:
     • Avoidance of thoughts, memories, and feelings about the traumatic event.
     • Avoidance of external reminders of the traumatic event (such as people and places)
  5. Arousal symptoms:
     • Sleep problems (such as difficulty initiating and maintaining quality sleep)
     • Irritability and rage attacks with minimum to no provocation
     • Highly and abnormally alert to surroundings
     • Distractibility
     • Unusually strong reflexive reactive to a sudden event in the environment
• C, D, and E: Duration of the symptoms should be between three days and four weeks and cause significant functional impairment and not related to substance use or other medical conditions (such as TBI) to meet the criteria for ASD.[16][17]

Evaluation

Acute stress disorder (ASD) is a psychiatric disorder but still can have physiological manifestations (such as tachycardia) and abnormal fMRI. However, no validated laboratory or radiographic test exists. The diagnosis is clinical and is based on history and physical examination. Careful behavior observation and careful listening to the patient's narrative are of immense value. Many patients are unable to fully reflect their feelings and history in the initial evaluation session and will require additional visits.

There are validated and quick psychometric questionnaires available that can be used to evaluate ASD children and adults. The Child Stress Reaction Checklist (CSDC), for example, measures symptoms of ASD and PTSD that can be completed in ten minutes. CSDC can be used for children 2 to 18 years old.[18] For adults, there is a questionnaire designed explicitly for ASD (i.e., acute stress disorder scale).[19]

Treatment / Management

General Measures

• Patient Safety- Making sure that the patient is safe after the traumatic event and knows where to seek help in case of an emergency (food and shelter).[20]
• Emotional Support- Patients can receive emotional comfort from close friends or family. In the absence of those, healthcare providers can provide support by explaining the prognosis, course, and coping skills for ASD.
• Practical Support- The process after a traumatic process can be overwhelming. This is because the patient will probably need to help with the police report of the incident, finding a provider, work leave of absence, and health insurance. In case of disability due to an accident, the patient might need further multi-modal medical support as well.
• Followups- Regular visits (for six months) for all patients with a significant traumatic event are recommended.[20]
• Suicidality- It is vital to evaluate patients for suicidality in each visit, especially in patients with risk factors for suicide or patients having comorbid psychiatric diseases (such as depression).[21]
(A1)

Psychotherapy - Treatment of choice for acute stress disorder (ASD) is a unique form of cognitive-behavioral therapy (CBT) called trauma-focused CBT. CBT can reduce the risk of further developing PTSD.[22] This evidence-based practice can be delivered via the internet, in person, or by phone. It focuses on increasing knowledge on trauma psychology, symptom management skills, identifying and disputing cognitive distortions, and exposure therapy. Exposure therapy is a CBT method that involves controlled patient exposure to the traumatic source to relieve the trauma memory mimicking fear extinction (discussed in the pathophysiology section). Exposure therapy is the standard of care for ASD (and PTSD). A transient worsening of the symptoms can appear, but it is not more common than other intervention methods.[2] Debriefing-which involves asking the patient to explain in detail, the trauma and their feeling about it in the first 72 hours is widely available. studies have not shown the efficacy of debriefing in preventing the development of PTSD, and debriefing is discouraged from routine administration to ASD patients.[23] Crisis intervention method with encouraging patients to avoid maladaptive coping behaviors (such as drinking alcohol).(A1)

Pharmacotherapy - Currently, there is no high-quality evidence for a pharmacotherapeutic agent for the treatment of ASD. Serotonin reuptake inhibitors (SRIs) and propranolol were trialed to prevent or treat ASD but were showed little evidence of efficacy.[24][25] Evidence for ASD pharmacotherapy is minimal, and most of the recommendations come from the research on PTSD.[2] Due to similarities between ASD and PTSD and having more RCTs on PTSD, we will review pharmacotherapies for PTSD, which can be applied to ASD. PTSD pharmacotherapy has been more effective in reducing mood symptoms, compared to recurrent memories and avoidance:(A1)

• Serotonin Reuptake Inhibitors (SRIs)- SRIs include Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). SRIs are the most studied medications for the treatment of PTSD with favorable results.[26] For example, paroxetine is FDA approved for the short treatment of PTSD and has shown significant treatment response compared to placebo in three RCTs.[26] Three SSRIs (fluoxetine, sertraline, and paroxetine) and one SNRI (venlafaxine) have the strongest evidence and are first-line pharmacotherapies for the treatment of PTSD.[27]
• Second-Generation Antipsychotics (SGAs)- Can be used either as monotherapy or augmentation with SRIs. Second-generation antipsychotics are not first-line and considered in patients who have limited response to SRIs and CBT, especially in the presence of associated anxiety and depression.[28] Pharmacotherapy should be started with small doses and gradually increased. In the absence of a clinical benefit, it should be gradually discontinued.
• Benzodiazepines- Benzodiazepines are not generally recommended for the treatment of PTSD. Benzodiazepines are ineffective in the prevention or treatment of PTSD. Benzodiazepine prescription is associated with significant adverse effects and worse outcomes and should be relatively contraindicated in PTSD patients.[29][30]
• Beta-Blockers- Studies show that propranolol therapy after an acute stressor did not change PTSD incidence but reduced sympathetic symptoms (such as tachycardia and sweating).[25] Current evidence is not strong enough to recommend its routine prescription for PTSD patients.
(A1)

Other Treatments - There is evidence that ECT is beneficial for PTSD patients with concurrent depression with the ability to reduce symptoms for both conditions.[31] It is suggested that one known side effect of ECT (i.e., memory disruption) could be used to help patients with severe PTSD.[31] Clinical trials on mood stabilizers (such as topiramate and tiagabine) are limited in number and quality.[32] Treatment arms were no better than the placebo or had limited effect size.[33] There are cases reports that lamotrigine or gabapentin were effective treatments for PTSD patient nightmares and flashbacks, but more evidence is required to support these medications.[34][33](A1)

Symptom Specific Treatments

• Sleep Disturbance- in the form of insomnia and nightmares are common in PTSD. Specific treatment of sleep disturbances might improve other symptoms of PTSD. Multiple studies have evaluated the efficacy of various pharmacotherapies. SRIs and benzodiazepines were not effective. Prazosin, which is an alpha-1 selective adrenergic blocker, has shown efficacy in the management of sleep disturbance in PTSD patients. Other adjuvant treatments, such as eszopiclone, olanzapine, and risperidone, have also been effective.[35]

Differential Diagnosis

The differential diagnoses of acute stress disorder (ASD) include but are not limited to the following:

• PTSD (symptoms last for more than four weeks)
• Adjustment disorder (does not meet the criteria for ASD)
• Brief psychotic disorder (also lasts less than four weeks and is stress-related. Symptoms are more generalized and usually less severe).
• Organic disorder such as mild traumatic brain injury (hard to distinguish based on the neurologic evaluation) or brain tumor (presence of focal neurologic deficit or headaches)
• Mood disorders such as major depressive disorder (predominance of low mood and depressive symptoms)

Pertinent Studies and Ongoing Trials

PTSD psychotherapy is the first-line treatment for PTSD/ASD but is not shown to be very efficacious. The lack of effective therapies continues to make PTSD a chronic illness. Therefore there is an immediate need to explore new compounds and approaches. One promising approach is the use of psychedelics such as ketamine, psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA) to treat PTSD.[36] In recent years, the FDA has approved breakthrough therapy designations for both MDMA and psilocybin to treat PTSD and depression.[36] One MDMA-assisted psychotherapy study is set to get the FDA's approval by 2022.

Treatment Planning

For patients with acute stress disorder (ASD), first-line management would be of trauma-focused cognitive behavioral therapy, as oral therapies have been found to be of limited benefit. Most of the studies on pharmacological treatment have focused on secondary prevention for PTSD rather than focusing on ASD.[37] However, oral medications have been found to be effective in PTSD.

Adult Pharmacotherapy

Selective Serotonin Reuptake Inhibitors (SSRIs) - SSRIs such as sertraline, paroxetine, and fluoxetine have been used to treat PTSD. FDA has only approved sertraline and paroxetine.

Two examples of SSRI pharmacotherapy are provided below:

1. Fluoxetine: Start with 20 mg/day, PO. If no clinical improvement in a month, gradually increase the initial dose by 5 mg every two to four weeks. The average dose in clinical trials is 40 mg/day. The maximum dose is 80 mg/day PO. Possible to divide the daily dose into two (one in the morning and one in the noon). The highest therapeutic dose tolerable to the patient can be tried for at least six weeks before deciding its efficacy.
2. Paroxetine: Start with 20 mg/day PO. If no clinical improvement in a month, gradually increase the initial dose of 10 mg every two to four weeks. The maximum dose is 60 mg/day. The highest therapeutic dose tolerable to the patient can be tried for at least six weeks before deciding its efficacy.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) - Venlafaxine (Effexor) extended-release has shown to be effective in PTSD treatment.[38] The extended-release oral form can be started at 37.5 mg once a day. The maximum dose is 300 mg once daily. Dose increases should be based on patient toleration and clinical improvement with no more than 75 mg/day increase in intervals of four or more days.

Second-Generation Antipsychotics (SGAs) - Two antipsychotics with the most clinical evidence are listed below:

1. Quetiapine monotherapy in an RCT started at 25 mg/day and increased to up to 800 mg/day, PO with an average dose of 258 mg/day. The results showed the clinician-administered PTSD scale (CAPS) as well as re-experiencing and hyperarousal scores in military and non-military cases. The final adjusted dose was 50-800 mg/day, with a patient count of 41. No patient dropouts in the treatment arm were due to inefficacy.[28]
2. Risperidone adjunctive therapy, in another RCT, did not show significant results in CAPS scores but showed a small reduction in hyperarousal and re-experiencing scores with a dose of up to 4 mg/day in military cases.[39]

 Alpha-1 Selective Adrenergic Blockers - Prazosin is an antihypertensive medication and works by blocking specific receptors on the vascular smooth muscle. It is thought that prazosin and its metabolites can reduce the overactivation of the sympathetic system in ASD and PTSD. Prazosin can be used as monotherapy or augmentation with an SRI to minimize sleep disturbances mainly.

1. Prazosin: start at 1 mg, PO at night with monitoring for hypotension (before and after the administration of prazosin). Gradually increase the dose for a final dose of 2 to 6 mg/night.[40]

Toxicity and Adverse Effect Management

SRI Side Effects - SRIs can cause long QT syndrome, SIADH, hyponatremia, suicide ideation (especially in children), seizures, increased risk of bleeding, sexual dysfunction, gastrointestinal symptoms (such as nausea, vomiting, and diarrhea), and serotonin syndrome. SRIs Should be prescribed by a professional and per guidelines.

Sexual dysfunction in the form of decreased libido, delayed ejaculation, and anorgasmia is common (25% to 73%) among women and men taking SSRIs.[41] Less than 10 percent of patients with sexual dysfunction due to SRIs therapy will improve after continued use of the SRI, and it is suggested to the first wait for up to 8 weeks for improvement. In the case of persistence, careful dose reduction can be tried. If the patient is still symptomatic for sexual side effects and has only partially responded to an SRI, it can be switched to another SRI. Augmentation with bupropion can be tried if the patient has had a good response to the SRI.[42] Please note that sexual dysfunction management recommendations are based on the research of depression treatment and not PTSD and ASD treatment.

SRIs should not be disconnected abruptly. This is to mitigate withdrawal symptoms.[43]

SRIs can cause mania in patients with bipolar disorder and should not be used in patients with a history of bipolar disorder. In the case of mania, SRI should be discontinued and appropriate bipolar disease therapy initiated. Sleep quality improved in four weeks.

SGA side effects - SGAs can cause long QT syndrome (all SGAs), metabolic syndrome (olanzapine, clozapine), anticholinergic symptoms, and extrapyramidal symptoms (EPS). EPS is less common with SGAs but still can occur:

1. Acute dystonia
2. Restlessness
3. Parkinsonism
4. Tardive dyskinesia

Risperidone can cause hyperprolactinemia. Clozapine can cause dose-related seizures and dangerous neutropenia. Regularly monitor neutrophil counts before and during the treatment.

Prazosin Side Effects - Prazosin can cause first dose orthostatic hypotension, dizziness, fatigue, and headache. Use caution in patients with hepatic function impairment.

Prognosis

According to one recent study, later development of PTSD is strongly associated with acute stress disorder (ASD). It also showed that an abnormal fMRI is associated with subsequent PTSD severity.[15] According to the DSM-5, PTSD remission occurs within three months in approximately half of the patients. It is recommended to continue pharmacotherapy for more than six months to one year to lessen the risk of relapse.[44] The majority of the patients who developed PTSD recover within the next few years, with a steep decline in the first year. At least one-third of the PTSD patients remain symptomatic for more than two years and are at risk of substance abuse.

ASD patients are 24 times more likely to die from a suicide attempt compared to those without ASD. One study found that all-cause mortality for patients with a stress disorder diagnosis is two times more than those without.[45]

Avoidance of many conditions that remind the patient of the traumatic event may continue to persist after the initial incident. For example, a car accident patient might avoid driving a car. The patient might lose their job due to abstinence from work or poor work performance. Resulting financial hardships can lead to homelessness in some cases. Social relationships can be limited and lead to break-ups with significant others, which would make the patient's emotional life, even more complicated.

Complications

Acute stress disorder (ASD) can lead to various psychiatric problems:

• Mood Disorders - Depressive disorders (with or without suicidality), anxiety and panic disorder
• Substance Use Disorders - alcohol use disorder and illicit drug dependence