Posttraumatic Stress Disorder: The Pharmacological Treatment Plan

ABSTRACT: Posttraumatic stress disorder is a severe condition that can develop after a person is exposed to one or more traumatic events. It commonly involves hyperarousal, flashbacks, serious injury, or even death, and is often combined with feelings of intense fear, helplessness, or horror. The first part of this article (Consultant, August 2013) introduced primary care clinicians to the history, diagnostic evaluation, epidemiology, biological causes, and psychosocial complications of PTSD. Now we review the biopsychosocial interventions used in treatment. 

Posttraumatic stress disorder (PTSD) is a trauma and stressor-related disorder that can develop after a traumatic event is witnessed or experienced. It commonly involves actual or threatened death, serious injury, or threat to a person’s physical integrity, combined with feelings of intense fear, helplessness, or horror. Patients with PTSD continue to exhibit symptoms of anxiety, hypervigilance, sleep difficulties, anger, and irritability, in addition to psychological numbness and interpersonal, social, educational, and vocational dysfunctions. They also remember and often relive the traumatic events.

An integral component of treating PTSD is psychoeducation. Patient education is important to both the patient and the family. It focuses on addressing the nature of PTSD in regard to its symptoms, course, and various triggers. In addition, it explores communication and problem-solving skills, as well as anger management. The education may occur in a variety of modalities, such as couples/family therapy, psychoeducational groups, support groups, and other available local and national community support organizations (eg, local veteran and national PTSD centers). 

Pharmacological Treatments

Medication is often necessary to reduce the severity of symptoms and is becoming an essential component of the overall management of PTSD. In addition to relieving core symptoms, pharmacological agents can improve associated feelings of anxiety, depression, and insomnia, which in turn helps better treat co-occurring psychiatric conditions. It can also enable patients to tolerate, contribute and participate in individual and/or group psychotherapy. It is important for primary care providers to evaluate the level of evidence supporting the medications they prescribe for PTSD treatment. 

Patients today have unlimited access to information through the internet and mass media advertisements. Therefore, outside factors—such as overzealous marketing, patient preferences, and a clinician’s particular custom that may be inconsistent with the evidence base—can influence prescribing patterns. 

Here is a review of the various pharmacological agents that have been used to treat PTSD:

Antidepressants. While no single pharmacological agent has emerged as the best treatment for PTSD, research and testimonials strongly recommend serotonin reuptake inhibitors (SRIs). The FDA has only approved two SRIs for the treatment of PTSD: sertraline and paroxetine.^1,2

In addition, the safety and efficacy of several other SRIs—fluoxetine, citalopram, escitaloptam, and fluvoxamine—have been tested in clinical practice.^3-7 Table 1 outlines the dosage, benefits, and side effects of various SRIs.^1-7 

Other medications. Off-label medications including antidepressants, atypical antipsychotics, adrenergic modulators/sympatholytics, and anticonvulsants/mood stabilizers are regularly used to modify the PTSD symptoms that do not respond to either sertraline or paroxetine. Antidepressants that are prescribed in the treatment of PTSD are also effective in treating co-occurring depression and anxiety disorders. 

Atypical antidepressants. These drugs that work through different mechanisms of action and/or other neurotransmitter combinations can also be helpful in PTSD treatment and these include: 

• Venlafaxin. This serotonin/norepinephrine reuptake inhibitor (SNRI) has also been shown to be beneficial in the treatment of PTSD.^3,4,6,8 It acts primarily as a serotonin reuptake inhibitor at lower dosages and as a combined serotonin and norepinephrine reuptake inhibitor at higher dosages. Although not FDA approved, clinicians have been increasingly using venlafaxin as a first-line treatment for PTSD over the last decade.⁹

• Mirtazapine.This antidepressant is a 5HT2/3 receptor blocker, which offers advantages including a modest potential for drug interactions, possible amelioration of nightmares, and less sleep disturbances.^3,4,6,10

• Trazodone. This antidepressant inhibits the uptake of serotonin, acetylcholine, norepinephrine, and dopamine, and is commonly used by many clinicians for the treatment of insomnia and nightmares in PTSD.^3,4,6,11

• Nefazodone. This is a unique serotonergic antidepressant that acts as both a presynaptic serotonin reuptake inhibitor and a postsynaptic 5-hydroxytryptamine 2A receptor antagonist.^12-14 Safety concerns relating to its hepatotoxicity and high potential for many drug interactions led to its market withdrawal in many countries. As such, this agent should not be considered as a routine management option for PTSD. The generic form of the drug is available in the US for limited use with patients who have previously not reported any adverse effects. The dosage, benefits, and side effects of atypical antidepressants are summarized in Table 2.^3-14

Tricyclic antidepressants (TCAs). TCAs are principally FDA-approved for the treatment of major depression (Table 3).^15-17 Studies have shown that the TCAs—imipramine, amitriptyline, nortiptyline, and doxepin—can be used to reduce the severity of self-reported PTSD symptoms and improve sleep.^15-17 The TAs side effects are summarized in Table 4.^15-17 Note: It is important for primary care providers to emphasize the fact that TCAs carry a greater risk of lethality in cases of accidental or intentional overdose. 

Monoamine oxidase inhibitors (MAOIs). Prescribed to severely depressed patients, particularly those unresponsive to TCAs, MAOIs—ie, phenelzine—have been used to reduce recurrent recollections of the trauma, nightmares, flashbacks, numbing, sleep disturbances, and social withdrawal in PTSD patients (Table 5).^18,19 Careful management of the MAOIs and strict dietary controls are important because they can cause potentially fatal hypertensive reactions when taken with other medications or tyramine-containing foods.¹⁹ 

Antipsychotic Medications

In the late 1980s, prior to the introduction and FDA approval of the SRIs treatment for PTSD, low-dose conventional or first-generation antipsychotics (FGAs) were sometimes prescribed for hypervigilance, exaggerated startle, and agitation associated with PTSD—even in the absence of such psychotic symptoms such as paranoia, delusions, and hallucinations. 

Atypical antipsychotics or second-generation antipsychotics (SGAs) soon followed. Although not evidenced and off-label, some clinicians are using SGAs as adjunctive agents for the treatment of chronic sleep difficulties, “flashbacks” or recurrent intrusive thoughts, sounds, and images of traumatic events, and “paranoid” ideas, such as the fear of being attacked when exposed in public places, agitation, anger, hypervigilance, exaggerated startle, and persistent depression.²² Metabolic syndrome, which is manifested by elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol, could develop among PTSD patients treated with the SGAs.²³ This syndrome could also be related to lifestyle factors and/or long-term overactivation of stress-response pathways.²⁴ Dosage and benefits of SGAs, such as risperidone, olanzapine, and quetiapine are summarized in Table 6.^25-28

Noradrenergic Agents

Also known as sympatholytic agents, adrenergic modulators, or adrenergic-inhibiting agents, the noradrenergic mechanisms help PTSD patients suffering from hyperarousal, anxiety, and memory functions. This class of medications includes prazosin, clonidine, and propranolol (Table 7).^29-37

• Prazosin. This α-1 adrenoreceptor antagonist is useful in reducing combat trauma nightmares, normalizing dreams for combat veterans with chronic PTSD, and stabilizing sleep disturbance associated with nightmares in non-combat-related chronic PTSD.^29-31

• Clonidine. This α-2 adrenoreceptor agonist reduces nightmares, hypervigilance, startle reactions, and outbursts of rage in the management of PTSD among some severely traumatized individuals.^29,32

• Propranolol. This ß-adrenergic blocker has also been considered for the treatment of hyperarousal.^29,33 Some studies suggest early treatment with propranolol after severe trauma may reduce the likelihood of subsequent development of PTSD, but additional research is still needed.^34-37

Anticonvulsants/Mood Stabilizers

The primary benefit of using the anticonvulsant mood stabilizers lies in the treatment of co-occurring PTSD and bipolar disorder. A range of different anticonvulsant agents have been considered as possible primary or adjuvant therapy for non-bipolar PTSD patients with refractory symptoms that have not responded adequately to other agents.¹⁹ This treatment is based on the known mood-stabilizing, antikindling and anger, aggression and rage modulating effects of the anticonvulsants.³⁸ Most of the studies have been conducted with topiramate, lamotrigine, carbamazepine, divalproex, and gabapentin.

• Topiramate. This anticonvulsant has demonstrated efficacy by significantly reducing re-experiencing phenomena, intrusive memories, nightmares, flash backs, sleep problems, irritability and anger, and startle reactions in some PTSD patients.^39,40 

• Lamotrigine. In certain patients with PTSD, lamotrigine was beneficial in decreasing the core symptoms of re-experiencing, avoidance, and psychological numbing.^41,42

• Carbamazepine. This anticovulsant may ameliorate persistent reexperiencing of the traumatic events,and was found to be helpful in combat veteran population by improving the PTSD symptoms—intrusive thoughts, flashbacks, and insomnia.³⁸

• Divalproex. This medication may ameliorate symptoms of avoidance and hyperarousal, and can lead to reduced irritability, mood lability, anger attacks, but not intrusive thoughts.^38,43

• Gabapentin. Some studies have shown that gabapentin can reduce the frequency of nightmares and insomnia.^44,45

Due to the high rate of co-occurring alcohol addiction and PTSD, the use of anticonvulsants could represent a novel primary care treatment approach targeted at symptoms of both alcohol addiction and PTSD. The anticonvulsants antagonizes alcohol's rewarding effects in alcohol addiction and regulates reexperiencing and arousal symptoms in PTSD.^39,41,46 

Based on current limited evidence, mood stabilizers and anticonvulsant medications cannot be recommended for the routine treatment of PTSD. Further research is required to establish the effectiveness and safety of mood stabilizers and anticonvulsant medications (Table 8^38-47) for PTSD patients. At present, no anticonvulsant agent has received FDA approval for use as a treatment for PTSD.⁴⁷

Antanxiety/Anxiolytic Agents 

Benzodiazepines. Despite the widespread use of benzodiazepines—eg, alprazolam, clonazepam, diazepam, and lorazepam—in treating anxiety symptoms, this class of medications should not be used in PTSD patients.⁴⁸ These patients may experience worsening of cognitive dysfunctions, concentration problems, memory difficulties, and behavioral disinhibition. There is currently no evidence in support of the efficacy or effectiveness of benzodiazepine in PTSD treatment.⁴⁸ 

According to various clinical guidelines, benzodiazepines should not be prescribed for PTSD except in rare conditions when used to treat co-occurring anxiety disorders—especially panic disorders that have failed to respond to non-benzodiazepine treatment.⁴⁹ Patients with PTSD and co-occurring substance abuse, as well as individuals with traumatic brain injury, would warrant particular caution and close monitoring if they are prescribed benzodiazepines.^50,51 It is important for clinicians to be aware of the markedly increased risk of intentional or accidental lethal overdose when these agents are combined with substance abuse, especially alcohol and opioid narcotics.

Buspirone (BuSpar). This anxiolytic agent has several advantages including a relatively benign side-effect profile and the lack of addictive potential because it does not cause significant physical dependency.⁵² Buspirone may take two or more weeks to alleviate PTSD symptoms. It has shown to effectively decrease intrusive thoughts and nightmares in some patients. The main benefit, however, is its action as an augmenting agent in potentiating antidepressants in treatment resistant depression.^48,53 

Sedative Hypnotics 

Sleep disturbances are often the most refractory symptoms in PTSD and, in fact, may at times be exacerbated by some of the antidepressants. The use of benzodiazepines for sleep is not recommended for PTSD.^47,50,54 The non-benzodiazepine hypnotic agents, antihistaminics, and other agents can be used as adjunctive treatment in the management of chronic sleep disturbances associated with PTSD. 

Developed in the late 1980s, these agents are indicated for short-term treatment of insomnia, however they have not been FDA approved for PTSD treatment. 

• Zolpidem. This agent should only be taken when at least four hours of sleep time are remaining, Driving should be delayed for at least one hour after waking and at least five hours after taking the extended release formula.⁵⁵

• Zaleplon. The shortest-acting hypnotic available due to its relatively short half life,^55,56 it may benefit patients who have difficulty falling asleep rather that those with frequent awakenings. 

• Eszopiclone. It may help improve both sleep maintenance and daytime alertness. Unlike other sedative hypnotics, eszopiclone is the first sleep medication approved to be taken long-term (up to six months) but is not indicated for PTSD patients.⁴⁸ 

• Ramelteon. Unlike other sedative hypnotics, ramelteon works by targeting melatonin receptors. However, in contrast to the above mentioned sedative hypnotics, ramelteon is not designated as a controlled substance.⁵⁷

Patients should be cautioned when first taking sedative hypnotics until they know how the medication may impact their alertness in performing morning activities. Note: Downward adjustment of the dose may be necessary when given with other CNS depressants. General side effects may include drowsiness, dizziness, fatigue, headache, unpleasant taste, and diarrhea. 

Sedative hypnotics also carry warnings including the possibility of morning drowsiness, memory lapses, and being unaware of completing actions, such as sleep-driving, making phone calls, preparing and eating food while asleep. These side effects occur at a higher incidence when the medications are taken above the recommended dose, or when combined with alcohol or other sedative hypnotics.⁵⁸ Anaphylactic reactions and facial angioedema can occur the first time these medications are taken.

Antihistaminic Agents

Diphenhydramine, hydroxyzine, or cyproheptadine can be temporarily used to induce drowsiness and sleep.⁵⁹ Their main side effects include drowsiness, day time sleepiness, and anticholinergic effects, such as dry mouth, blurred vision, constipation, urinary retention, exacerbation of asthma and breathing difficulties, cognitive impairment and dizziness. Additive central nervous system (CNS) depressant effects may occur when antihistaminics are combined with other sedating pharmacological agents. It is important to know that some patients taking antihistaminics may experience hyper excitability and stimulation leading to their potential for being abused. The most commonly prescribed sedative are summarized in Table 9.^48-59

Although the pharmacological treatment of PTSD is mainly targeted at three areas—hyperarousal, avoidance/numbing, and re-experiencing—in addition to other co-occuring psychiatric conditions, one class of medication may not always effectively treat all the presenting conditions. In some complicated PTSD cases and in patients with co-occurring medical and psychiatric conditions, the combination of various classes of psychiatric medications may be needed to accomplish a successful treatment outcome. The October issue of Consultant will highlight psychological treatment options for PTSD.

Acknowledgments: The author thanks Dr Avak Howsepian for his constructive criticisms; the VA Central California Health Care System Medical Center Director Joanne M. Krumberger, FACHE, for her administrative and leadership support; Chief of Staff Dr Wessel Meyer for his clinical support; Dr Peter Watson for his encouragement; Dr Margaret Aimer for her supervision; Drs Robert Hierholzer, Nestor Manzano, Scott Ahles, and Craig C. Campbell for their academic guidance; and Dr Matthew Battista and Mr Leonard Williams, PA, for their encouragement. ■

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Hani Raoul Khouzam, MD, MPH, FAPA is a health sciences clinical professor of psychiatry at the University of California San Francisco (UCSF) Fresno Medical Education Program and a psychiatrist at the VACCHCS in Fresno, Calif. He is a consultant psychiatrist in Matariki/ counties Manukau, New Zealand.