Hani Raoul Khouzam, MBBCh, MPH
From the Veterans Affairs Central California Health Care System and the UCSF Fresno Medical Education Program, Fresno, CA.
• Objective: To review pharmaceutical agents studied for the treatment of posttraumatic stress disorder (PTSD).
• Methods: Review of the literature.
• Results: Evidence exists that pharmacotherapy can provide relief for the 3 core symptom clusters present in PTSD: reexperiencing, avoidance/numbing, and hyperarousal. The selective serotonin reuptake inhibitors are considered first-line pharmacotherapy for PTSD, although results are conflicting with respect to treatment of combat-related PTSD. The addition of other medications may be required to address specific aspects of the symptom spectrum and to treat co-occurring psychiatric conditions.
• Conclusion: There is a need for additional randomized controlled trials to confirm the effectiveness of pharmacologic treatment of PTSD.
Posttraumatic stress disorder (PTSD) is a common and disabling disorder that affects an estimated 7.8% of the U.S. population [1,2]. The lifetime prevalence of PTSD in the general community is 8% to 9%, and the 12-month prevalence of PTSD is nearly 4% [2,3]. Women have a higher lifetime prevalence (10% to 14%) than do men (5% to 6%) . In primary care settings, as many as 12% of patients meet criteria for either partial or full PTSD . In mental health treatment–seeking populations, the prevalence of PTSD may be as high as 40% to 50% .
The risk of PTSD varies by trauma experienced. The most common trauma-related risks for men are rape, combat exposure, childhood neglect, and childhood physical abuse ; for women, rape, sexual molestation, physical attack, being threatened with a weapon, and childhood physical abuse are the most common . Assaultive violence in general demonstrates the highest probability (> 20%) of leading to PTSD whereas learning about traumatic events to others carries the lowest probability (2%) [2,3,6]. About 30% of men and women who have spent time in war zones experience PTSD, with an additional 20% to 25% experiencing partial PTSD at some point in their lives . More than half of all male Vietnam veterans and almost half of all female Vietnam veterans have experienced “clinically serious stress reaction symptoms” . PTSD has also been detected among veterans of the Gulf War, with some estimates running as high as 8% . The prevalence rates after deployment to Iraq and Afghanistan have been estimated at 6% to 13% . In the largest cohort of civilian survivors of the World Trade Center attacks assembled to date, it was found that the majority of survivors experienced multiple 9/11-related PTSD symptoms 2 to 3 years after the attacks .
The 3 core symptom clusters present in PTSD are reexperiencing, avoidance/numbing, and hyperarousal. The full DSM-IV-TR diagnostic criteria of PTSD are shown in Table 1 . PTSD is responsive to pharmacotherapy and psychotherapy. In this paper, agents studied for the treatment of PTSD are reviewed.
Research into the effectiveness of antidepressants for the pharmacotherapy of PTSD began in the 1980s, with the use of the nonselective monoamine oxidase inhibitor (MAOI) phenelzine . The MAOIs’ interaction with various many medications and dietary restriction with tyramine-containing foods and drinks limited their clinical usefulness. Research interests turned to the tricyclic antidepressants (TCAs), which were found to reduce PTSD symptoms . The TCAs have the disadvantage of toxicity in overdose (with evidence suggesting that patients with PTSD have a high risk of suicide attempt by overdose) and have unfavorable adverse effects, especially in regard to their anticholinergic effects, which are particularly risky for patients with history of co-occurring heart disease, cognitive disorders, and prostatic hypertrophy [13,14]. In contrast to the MAOIs and the TCAs, the serotonergic reuptake inhibitors (SSRIs) offer a broad spectrum of action on reducing PTSD symptoms and as a class are generally well tolerated [13–15].
Selective Serotonin Reuptake Inhibitors
The SSRIs are the most studied medications for PTSD. In a Cochrane review of 35 randomized controlled trials (RCTs) of PTSD with 4597 participants that examined the effects of medication for PTSD , the authors concluded that while no clear evidence exists to show that any particular class of medication is more effective or better tolerated than any other, the greatest number of trials showing efficacy to date, as well as the largest, were with SSRIs. The authors supported SSRIs as first-line agents in the pharmacotherapy of PTSD and supported their value in long-term treatment .
Although the effects seen in RCTs have established SSRIs as first-line therapy, results are conflicting with respect to treatment of combat-related PTSD, with some veterans responding well but the majority requiring other classes of medications or requiring combinations of various agents . The low response rate to SSRIs in combat veterans has been attributed to several conditions, especially the presence of co-occurring depressive disorders, other anxiety disorders, substance abuse, and other co-occurring medical conditions . It is important to assess response of each symptom as well overall response in determining the effectiveness of SSRI treatment in combat veterans. For example, the SSRIs seem neither to improve insomnia nor reduce recurrent nightmares and could even be expected to exacerbate sleep difficulties in PTSD, since they are most commonly associated with acute rapid eye movements (REM) sleep without atonia and sleep behavior disorder, and patients with PTSD may display heightened motor activation during REM sleep, possibly worsening or exacerbating PTSD .
The SSRIs’ mechanism of action is presumed to be related to the inhibition of the neuronal uptake of the neurotransmitter serotonin (5-HT) leading to the potentiation of serotonergic activity in the central nervous system (CNS). They have varying degrees of selectivity for other neurotransmitters. They have a very weak effect on norepinephrine and dopamine neuronal reuptake and they do not inhibit MAO. Most SSRIs have no significant affinity for α1, α2, and ß adrenergic, cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs [14–19]. The 3 SSRIs most extensively studied are discussed below.
Sertraline [19–22] was approved for the treatment of PTSD in 1991. Treatment with sertraline usually begins at a dose of 25 mg/day, which is increased to 50 mg/day after 1 week. Further dosage titration in 50-mg increments at weekly intervals may proceed to a maximum dose of 200 to 250 mg/day. Dose changes should not occur at less than weekly intervals as it takes at least that length of time to achieve steady-state concentrations. It may take 4 to 6 weeks to see an initial response to treatment.
The most common side effects of sertraline include upset stomach, trouble sleeping, diarrhea, dry mouth, sexual side effects, fatigue, tremor, indigestion, increased sweating, feeling agitated, and decreased appetite. Sertraline offers several advantages in treating PTSD, including improved patient tolerability, low risk of lethality in overdose, and no dependence potential. It is also as well-tolerated as other SSRIs and may even have a more favorable side effect profile due to its low potential for pharmacokinetic effect on the cytochrome P450 system, thus minimizing the possibility of drug interactions with other medications that are metabolized through that system.
Paroxetine was approved for the treatment of PTSD in 1992. Initial treatment is usually 20 mg/day in the morning; dose may be increased by 10-mg/day increments at intervals of at least 1 week. Doses of 20 and 40 mg/day of paroxetine are effective and well tolerated in the treatment of adults with chronic PTSD [23,24]. Higher doses may be needed in patients with co-occurring depression/anxiety. Dose adjustments should be made to maintain the patient on the lowest effective dose, and patients should be periodically reassessed to determine the need for continued treatment. The most commonly observed adverse events associated with the use of paroxetine include asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, decreased libido, and erectile dysfunction.
Fluoxetine [25–28] is usually dosed 10 to 20 mg/day for 1 week, then increased to 20 mg/day. Doses up to 60 mg daily may be considered after several weeks if there is no clinical response. The most common side effect is nausea during the first 2 weeks of treatment; nervousness and anxiety also are also common. Because of its long half-life, fluoxetine side effects may last for several weeks even after its discontinuation [16,29,30].
In summary, the SSRIs should be regarded as first-line pharmacotherapy for PTSD; however, the addition of other medications may be required to address specific aspects of the symptom spectrum [16,28,30]. The SSRIs differ primarily in their pharmacokinetics, metabolic effects on other medications, and side effects rather than in their efficacy in treating PTSD. Because the SSRIs are involved in many significant drug-drug interactions, this issue must be considered and accommodated when designing a pharmacologic treatment that includes other agents that may be used for co-occurring psychiatric and medical conditions [13–16,28,30]. Discontinuation ofSSRIs should be accomplished by gradual tapering with carefulobservation, especially during the first 2 months, to reducethe risk of relapse and to avoid cumbersome adverse effects related to the SSRI interruption/discontinuation syndrome .
Serotonin Norepinephrine Reuptake Inhibitors
Two double-blind placebo-controlled trials involving civilian patients showed venlafaxine extended-release to be effective in improving PTSD symptoms [31,32]. In the study that was also sertraline-controlled , venlafaxine performed as well as sertraline. Venlafaxine is effective in treating PTSD core symptoms, has good tolerability, and is considered an alternative first-line option to SSRIs. Its mechanism of action is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. It has no significant affinity for muscarinic, histaminergic, or α1 adrenergic receptors. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropics. It does not possess MAOI ctivity. Venlafaxine can be given either in the immediate- or extended-release formula [13–16,30,33].
The immediate-release tablets are usually started at 75 mg/day (2 to 3 divided doses); dose may be increased by 75 mg/day every 4 days to a maximum dose of 225 mg/day. The extended-release capsules and tablets formula dose is 37.5 to 75 mg/day (single dose); dose may be increased by 75 mg/day every 4 days to a maximum dose of 225 mg/day. Side effects include weakness, sweating, nausea, constipation, vomiting, drowsiness, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision and sexual dysfunction. A rare adverse effect is hypertension [13–16,33].
Duloxetine was studied in a 12-week, open-label, flexible-dose trial of monotherapy in veterans with PTSD . The mean daily dose of duloxetine was 81 mg. Nine participants (45%) were classified as responders, defined by a 20% or greater improvement in symptoms. Most of the improvement was observed by week 2 of treatment. The most common side effects were diarrhea (25%), constipation (20%), and nausea (20%). Two subjects developed tachycardia, and one withdrew from the trial for this reason. Duloxetine had a quick onset of action and was well tolerated by most of the study subjects. Given these preliminary results, a double-blind, placebo-controlled study in a difficult-to-treat PTSD population is warranted.
Other Second-Generation Antidepressants
Nefazodone has been studied in several RCTs and case-control studies. It has been shown to be more effective than placebo in improving PTSD symptoms [16,35–39] and was shown to be equivalent to sertraline in a fair-quality trial . Its mechanism of action is distinct from that of other antidepressants, in that it potently and selectively blocks postsynaptic 5-HT and 5-HT2A receptors and moderately inhibits serotonin and norepinephrine reuptake [35,41]. It has a lower incidence of anticholinergic, antihistaminergic, and adrenergic effects, and compared with SSRIs causes fewer activating symptoms, fewer adverse gastrointestinal effects, and fewer sexual side effects, but is associated with more dizziness, dry mouth, constipation, visual disturbances, and confusion. It is not associated with abnormal weight gain, seizures, priapism, or significant sleep disruption [35,41].
The initial dose is 100 to 200 mg/day given in 2 divided doses at intervals of no less than 1 week with a maximum dose of 600 mg/day. Due to safety concerns related to hepatotoxicity and inhibition of the cytochrome P450 3A4 isoenzyme system, nefazodone is rarely used in PTSD except in a few cases where it was the only effective treatment for patients who did not develop side effects secondary to its use [16,30,35,41].
Trazodone has not been proven significantly effective in management of the core symptoms of PTSD [16,30,41,42]. Because of its sedative effects, some clinicians prescribe it in low doses to treat PTSD patients with sleep difficulties. It selectively inhibits serotonin uptake and potentiates the behavioral changes induced by the serotonin precursor 5-HT and does not stimulate the CNS. It is available in immediate- and extended-release tablets. The immediate-release tablets initial dose is 150 mg/day in divided doses; may increase dosage by 50 mg/day every 3 to 4 days with a maximum average dose of 400 to 600 mg/day. The extended-release tablets initial dose is 150 mg once daily in the evening, preferably at bedtime; it may be increased by 75 mg once/day every 3 days with a maximum dose of 375 mg/day, which may be gradually reduced once adequate response achieved. The undesirable side effects of trazodone include orthostatic hypotension, arrhythmias, and priapism. Side effects need to be closely monitored, especially in patients with co-occurring medical conditions.
Two trials with mirtazapine have demonstrated positive findings. In the placebo-controlled trial , mirtazapine was more effective than placebo on some measures in PTSD and general anxiety symptoms, but both mirtazapine and placebo had large effect sizes. In a trial of Korean veterans, mirtazapine was found to be as efficacious as sertraline, but there was no placebo comparison arm .
Mirtazapine has a favorable effect on sleep and a modest potential for drug interactions with absence of serious adverse effects. It enhances central noradrenergic and serotonergic activity. It acts as an antagonist at central presynaptic α2 adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity [16,30]. It is a potent antagonist of 5-HT2 and 5-HT3 receptors. It has no significant affinity for the 5-HT1A and 5-HT1B receptors. It is a potent antagonist of histamine (H1) receptors, a property that may explain its prominent sedative effects [16,30]. It is a moderate peripheral α1 adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use [16,30]. It is also a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use. The usual dose is 15 mg/day at bedtime and may increase in dose every 1 to 2 weeks to a maximum dose of 45 mg/day. The main side effects of mirtazapine include sedation, constipation, and weight gain [16,30].
Of the TCAs, only amitriptyline and imipramine have been shown to be beneficial in PTSD by alleviating avoidance and numbing and improving sleep [41,44–47], while data on desipramine and nortriptyline have been negative and from poor quality studies [47,48]. These agents may still have a place as an option in the management of core PTSD symptoms. The main concern related to the TCAs is their adverse effects, which include their oversedating properties and their cardiovascular effects, including orthostatic hypotension, tachycardia and cardiac conduction slowing. Also problematic is the potential lethality of TCAs in overdose. Because of their side effects, the TCAs are not commonly used in PTSD treatment.
Monoamine Oxidase Inhibitors
Of the currently available MAOIs, only phenelzine has been studied [46,50]. In a placebo comparison trial, Vietnam veterans assigned to phenelzine had significant improvement, with a 60% average reduction in intrusive thoughts compared with placebo . Phenelzine is a potent nonselective MAOI that exerts its clinical effects by elevating CNS levels of the catecholamines 5-HT and GABA [13,16]. The main side effects include daytime sleepiness, dizziness or lightheadedness, hypotension, diarrhea, dry mouth, altered sense of taste, nervousness, muscle aches, insomnia, erectile dysfunction, and paresthesia [13,16]. Phenelzine dose is 15 mg every morning for 4 days, then increased gradually over 2 weeks as needed and tolerated up to 60 to 90 mg/day [13,16].
The main obstacle in prescribing MAOIs is the strict dietary restriction in order to prevent the development of hypertensive crisis when taken in combination with foods that are rich in tyramine. Another risk is the development of serotonin syndrome when taken in combination with other serotonergic medications, thus requiring a washout period of at least 2 weeks prior to initiating MAOI treatment, except for fluoxetine, which requires 5 weeks.
A number of small single-site studies suggested that atypical antipsychotic agents were effective adjunctive treatment for PTSD patients who had poor responses to the SSRIs or SNRIs. Studies of risperidone yielded mixed results, with several RCTs showing superiority to placebo as adjunctive therapy and some showing no effect [49–52]. Recently, a large-scale multisite VA trial of risperidone as an adjunctive agent for poor or partial responders to SSRI/SNRI antidepressants showed some symptom cluster improvement, but the overall result was negative in comparison with placebo . In an open trial of adjunctive therapy with quetiapine, some decrease in the PTSD symptoms of reexperiencing, hypervigilance, exaggerated startle, agitation, and sleep problems was documented . In a double-blind, placebo-controlled study in 2002, olanzapine augmentation was associated with statistically significantly greater reduction than placebo in specific measures of posttraumatic stress, depressive, and sleep disorder symptoms, but there was no difference in clinician-rated global response rates .
With regard to monotherapy, in a small pilot study  olanzapine fared no better than placebo, but a 2012 placebo-controlled study showed efficacy of olanzapine as monotherapy in a non–combat-related PTSD population . Overall, there is insufficient evidence at this time to recommend atypical antipsychotics as adjunctive therapy for PTSD.
Atypical antipsychotics must be used with caution and requires monitoring for metabolic syndrome, as they may cause elevation of blood glucose levels and cholesterol levels and can lead to the development of diabetes and hyperlipidemia in addition to weight gain [58–60]. There is also a small risk of developing extrapyramidal side effects and tardive dyskinesia and more rare side effects such as the neuroleptic malignant syndrome. In addition, all atypical antipsychotic medications have a black box warning of increased risk of death compared with placebo if given to elderly patients with dementia-related psychosis. Although the causes of death were varied in clinical trials, most of the deaths appeared to be either cardiovascular due to heart failure or sudden death or infectious in nature due to pneumonia.
Evidence for the use of antiadrenergic agents as a treatment strategy for the management of PTSD appears promising, but more RCTs addressing this approach must be undertaken before their use can be advocated in the routine treatment of chronic PTSD [16,61,62]. Antiadrenergic agents in general can reduce the peripheral manifestations of hyperarousal and may reduce aggression and can also be used for co-occurring performance anxiety and social phobia [61–63]. These medications should be prescribed judiciously for patients with cardiovascular disease because they may lead to a reduction in normal range of blood pressure and could induce rebound hypertension if blood levels fall due to infrequent dosing or a sudden discontinuation. Furthermore, these agents should not be frequently prescribed for patients with diabetes as they may interfere with the hormonal responses to hypoglycemia [16,61–63].
Evidence from RCTs indicate that prazosin is effective for treatment of PTSD-related nightmares [62–64]. While the specific mechanism is unknown, it is hypothesized that by blocking the α1-adrenoceptor in the central nervous system, it decreases nightmares that result from increased adrenergic responsiveness in PTSD. It blocks the effects of norepinephrine release from noradrenergic neurons, such as those originating within the locus ceruleus of the brainstem. Despite prazosin’s established usefulness for reducing nightmares, results have been mixed regarding its efficacy for the treatment of other PTSD core symptoms.
The optimum prazosin dosage in PTSD treatment has not yet been established. In clinical studies, the usual initial dosage is 1 mg at bedtime which is then gradually increased based on patient’s response and tolerance. Some experts recommend a target maintenance dosage of 1 to 10 mg daily; others recommend a higher target dosage of 2 to 20 mg daily [28,65]. Hypotension is the main side effect to monitor when initiating prazosin, and although this has not proven to be a problem for most patients receiving this medication, a slow titration is recommended for patients without co-occurring hypertension. Other side effects include vertigo, nervousness, frequent urination, and nose bleeds. It can also cause dry mouth, nasal congestion, tachycardia, hallucinations, incontinence, impotence, ringing in ears, fever, sweating, and muscle pain .
Clonidine, a noradrenergic α2 agonist, has not been evaluated in an RCT. It has shown some beneficial effects in decreasing PTSD-associated symptoms of explosiveness, sleep problems, nightmares, startle, hyperalertness, and intrusive thinking. Most patients respond to treatment with clonidine 0.2 mg three times/day, titrated from 0.1 mg at bedtime. Patients’ blood pressures should be checked periodically when this agent is used for long-term therapy since it can cause hypotension [16,66].
Guanfacine (Tenex, Intuniv)
This pre-synaptic α2 agonist was studied in 2 trials and no effect was seen on measures of PTSD symptom severity for the actively treated group relative to the placebo group [67,68].
This sympatholytic nonselective β-blocker was used in some clinical trials in acute trauma aftermath in order to evaluate its effects on diminishing the consolidation of traumatic memories and attenuating the course of posttraumatic symptoms and evolving PTSD [69–71]. In these trials, patients were treated with propranolol for 7 to 10 days within 6 hours of the trauma and assessed 1 to 2 months following their initial trauma. The results showed propranolol to have a PTSD preventive effect, although these findings were not very robust [70,71].
Initial dose of propranolol is usually 40 mg orally twice daily or 80 mg sustained release once daily. However, the dose that was used in PTSD treatment was 40 mg three or four times/day for a period of 7 to 10 days administered shortly after trauma exposure [71,72]. The side effects of propranolol may include constipation, diarrhea, dizziness, drowsiness, fatigue, lightheadedness, nausea, stomach upset or cramping, trouble sleeping, and vomiting.
MOOD STABILIZERS AND ANTICONVULSANTS
An interest in the therapeutic role of mood stabilizers and anticonvulsants in treating PTSD developedfrom the recognition of the possible role of neuronal sensitizationand kindling in the pathophysiology of PTSD, along with thehigh prevalence of impulsivity among those with the disorder [73–79]. The existing evidence does not support the use of anticonvulsants as monotherapy for the management of PTSD core symptoms, but they are frequently used as adjunctive treatments.
Carbamazepine (Tegretol, Equetro)/Oxycarbamazepine (Trileptal)
In open-label trials, carbamazepine was associated withreductions in intrusive traumatic memories and flashbacks and improvements in insomnia, irritability, impulsivity, andviolent behavior [73,74]. The initial dose is 200 mg every 12 hours or 100 mg following autoinduction. Higher doses will be necessary to maintain drug levels within the therapeutic range of 6 to 12 mcg/mL. The daily dose can be increased in 100 to 200 mg increments at 1-to 2-week intervals and the maintenance dose can be increased up to 1200 mg daily in 3 or 4 divided doses . Potentially life-threatening reactions to carbamazepine involve aplastic anemia, toxic hepatitis, pancreatitis and skin reactions, specifically Stevens-Johnson syndrome and toxic epidermal necrolysis.
Valproate (Depacon), Divalproex (Depakote)
Valproate has been associated with improvement in arousal and avoidance in some trials [75,76].In a large RCT that evaluated valproate as monotherapy for its efficacy in treating veterans with PTSD, with a focus on hyperarousal symptoms, there were no significant differences in primary or secondary outcomes between the patients receiving the medication and the placebo group . Initial dose is usually 750 mg daily in divided doses, which can be increased as tolerated and based on clinical response to achieve the desired range of plasma concentrations between 50 and 125 mcg/mL. Maximum concentrations are generally achieved within 14 days. This medication can cause acute hepatitis with liver failure, acute pancreatitis and can lead to polycystic ovarian syndrome. It also may cause birth defects in pregnant women.
An open-label trial in a civilian population showed that topiramate, administered alone or as adjunctive treatment, was associatedwith reductions in PTSD symptoms, including severe nightmares . However, a later RCT conducted in male veterans with PTSD showed no difference between topiramate and placebo . Most commonly, topiramate is started at low doses, 25 or 50 mg per day, and then increased slowly by 25 to 50 mg per week until an effective daily dose is reached. It is important to drink an adequate amount of water daily to avoid the side effect of developing of kidney stones.
In a small preliminary study, lamotrigine was associated with improvement in reexperiencingand avoidance/numbing relative to placebo in PTSD patients. However, becauseof the small study sample, the finding was not statistically significant . Lamotrigine is usually initiated at a dose of 25 mg daily, which can be gradually increased as tolerated up to 200 mg daily. It can be given all at once in divided doses twice or 3 times daily. Its efficacy may be affected by oral contraceptives containing estrogen. Although most patients who develop a rash while receiving lamotrigine have mild to moderate symptoms, some individuals may develop the serious skin reaction of Stevens-Johnson syndrome, which would require immediate emergency hospitalization.
An adjunctive therapy for PTSD, gabapentin was found in a clinical series to be helpful for improving insomnia and also for reducing the frequencyof nightmares . However, in an RCT in which the drug was administrered within 48 hours of acute physical injury, it showed no benefit over placebo in treating PTSD core symptoms . The initial dose is 300 mg orally on day 1, 300 mg twice a day on day 2, then 300 mg 3 times a day on day 3. The dose may be titrated up as needed for symptom relief up to 900 to 1800 mg in 3 divided doses to a daily maintenance dose of 1800 mg. No additional benefit was demonstrated from the use of doses over 1800 mg/day. Some side effects of gabapentin, while occurring infrequently, are potentially serious and may include depression, hostility, severe dizziness, confusion, or coordination problems that do not improve with time. In addition, an allergic reaction, including unexplained rash, hives, itching, and unexplained swelling, could occur.
This anticonvulsant was compared with placebo in 2 RCTs; no differences were seen in PTSD symptom response [83,84].
Lithium (Eskalith, Lithobid, Lithonate, Lithotabs)
Case studies and clinical trials suggest that the addition oflithium may be helpful for reducing angerand irritability among patients with PTSD . The usual dose is 1800 mg/day usually given in 3 divided doses, then given once daily if well tolerated. Serum levels should be determined twice per week during the acute phase and until the serum levels and clinical condition of the patient have been stabilized. Desirable serum lithium levels are 0.6 to 1.2 mEq/L, which can usually be achieved with 900 to 1200 mg/day. Serum lithium levels in uncomplicated cases should be monitored at least every 2 months. Elderly patients often respond to reduced dosage and may exhibit signs of toxicity at serum levels ordinarily tolerated by younger patients. Giddiness, blurred vision, tinnitus, severe shakiness, and seizures are some of the serious effects of lithium. Patients with thyroid or kidney problems should avoid taking lithium. A low-sodium diet is contraindicated in lithium therapy and adequate hydration is necessary to prevent lithium toxicity.
In summary, the existing evidence does not support the use of anticonvulsants/mood stabilizers as monotherapy for PTSD treatment. They can be used as adjunctive treatments for co-occurring PTSD and bipolar disorder. Clinicians should accurately document the rationale for using these medications as adjunctive agents for treatment-resistant chronic PTSD and need to be keenly aware of the side effects of each agent in this class of medications.
Although the benzodiazepines belong to the anxiolytic class of medications and are widely used for symptomatic relief of insomnia, panic, anxiety and irritability, their use should be discouraged in PTSD due to the lack of evidence for their effectiveness in reducing PTSD core symptoms, and the risks associated with their use outweigh any potential benefits they have in reducing PTSD-associated anxiety [86,87]. There is evidence to suggest that benzodiazepines may actually potentiate the acquisition of fear responses and worsen recovery from trauma [16,86,87]. Benzodiazepine use should be considered relatively contraindicated in combat veterans with PTSD because of the very high co-occurrence of combat-related PTSD with alcohol and substance use disorders, potential complications due to the development of tolerance, dependence, and significant withdrawal symptoms if they are discontinued [87–89]. Studies involving different animal models of PTSD have shown that benzodiazepine administration in the immediate aftermath of stress exposure significantly increases vulnerability of developing more severe responses upon subsequent exposure to stress .
This non-benzodiazepine anxiolytic was reported to improve PTSD symptoms in 2 very small studies [91,92]. Its effectiveness remains to be established in RCTs. Buspirone can been used to augment antidepressants in refractory co-occurring major depression and PTSD [16,30,31]. Buspirone is a 5-HT1A receptor agonist with a lowpotential for abuse and withdrawal symptoms . Buspirone is usually given at the dose of 5 mg 2 to 3 times a day and may be increased by 5 mg/day every 2 to 3 days as tolerated with an average of 20 to 30 mg/day in 2 to 3 divided doses with a maximum dose of 60 mg/daily. Main side effects include nausea, excitement, headache, numbness, feelings of nervousness and hostile behavior .
Because sleep complaints are common and have a direct impact on PTSD treatment outcomes, clinicians may consider using non-benzodiazepine hypnotics like zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta), and ramelteon (Rozerem), or antihistaminics like hydroxyzine (Vistaril, Atarax), cyproheptadine (Periactin), and diphenhydramine (Benadryl). There are no RCTs that support use of these agents for the treatment of PTSD [16,94]. In addition, the side effects of these agents are not well tolerated [47,94]. Patients with PTSD and co-occurring sleep disorders need to be evaluated to determine the cause of their sleep disorders. If sleep difficulties is a feature of their PTSD core symptoms, then further evaluation of their pharmacological treatment would need to be pursued [16,47,94].
Guidance for Prescribing
In general, patients diagnosed with PTSD should be offered an SSRI or an SNRI [Table 2]. If patients do not respond to these medications, then mirtazapine, a TCA such as amitriptyline or imipramine, the MAOI phenelzine, or nefazodone should be considered. The use of mood stabilizers, atypical antipsychotics, or prazosin are not indicated as monotherapeutic agents for PTSD but could be used as adjunctive agents for treating associated mood symptoms, sleep disturbance, nightmares and co-occurring psychiatric conditions. Clinicians should avoid prescribing benzodiazepines as well as other sedative and hypnotic medications for PTSD treatment.
Prior to initiating pharmacologic treatment of PTSD, the risks and benefits of treatment should be discussed. To maximize adherence to treatment in the acute phase, clinicians should give simple educational messages regarding medication use (eg, take daily, understand gradual nature of benefits, continue even when feeling better, medication may cause some transient side effects) along with specific instructions on how to address issues or concerns and when to contact the provider. Patients may be taking several medications concurrently, which raises the risk of adverse effects due to drug-drug interactions, and this could further be complicated in patients who also abuse alcohol or illicit drugs. With these factors in mind, it is critical that patients receiving pharmacotherapy for PTSD be monitored closely to ensure that treatment-related morbidity is minimized and clinical outcomes are optimized.
It is recommended to allow sufficient response time (at least 8 weeks) before changing a medication. If there is some decrease in PTSD symptoms and patients are tolerating the medication, it should be continued for at least another 4 weeks. If the medication is not tolerated, another effective medication should be tried. If there is no improvement at 8 weeks, clinicians should consider increasing the dose to the maximum tolerated amount. Clinicians should assess medication adherence and monitor for side effects at follow-up appointments. Managing any side effects will reinforce medication adherence and may prevent the development of adverse or irreversible complications.
Due to the chronicity of PTSD, responders to pharmacotherapy may need to continue medication indefinitely; however, it is recommended that maintenance treatment be periodically reassessed.
It is important for clinicians treating PTSD patients to be aware that all antidepressant medications have been associated with increased risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies, but no increase in the risk of suicidality compared with placebo in adults beyond age 24 . There is actually a reduction of suicidal risk compared with placebo with antidepressants in adults aged 65 and older. The risk of suicide must be balanced with the patient’s clinical need. It is important to monitor patients closely for clinical worsening of symptoms, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the medication prescribers .
Medications can be effective in the treatment of PTSD. Although this review was limited to pharmacotherapy for PTSD, the treatment of PTSD often requires a multidimensional interdisciplinary approach that includes pharmacologic, psychosocial, and spiritual interventions. Although a 2008 Institute of Medicine report concluded that when compared with medications, the evidence is stronger for the effectiveness of psychotherapy in PTSD treatment , several clinical studies have concluded that for patients with PTSD and co-occurring psychiatric conditions, especially depression and anxiety, the benefit of medications over placebo is substantial in stabilizing PTSD in these patients. There is a need for additional RCTs of current and future medications to improve patient outcomes in this chronic disabling condition.
Acknowledgments: The author thanks Dr. Avak A. Howsepian for his inspiration and staff at the Cottage Community Mental Health Center and Counties Manukau District Health Board, Auckland, NZ.
Corresponding author: Hani Raoul Khouzam, MBBCh, MPH, Matariski-The Cottage, PO Box 22328, Otahuhu, Auckland 1640, NZ, firstname.lastname@example.org.
Financial disclosures: None.
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