Ctsma.org

CONTINUING EDUCATION
Post-Traumatic Stress Disorder Current
Approach to Treatment
by Chris Paxos, PharmD, BCPP, CGP; and Sara E. Dugan, PharmD, BCPP
event. Similar to variations in exposure to traumatic events, the prevalence of PTSD also has been found to vary wide- ly. It is estimated that the lifetime prevalence of PTSD in the Utraumatic stress disorder. general population is 5-6 percent for males and 10-14 per- cent for females. For populations exposed to interpersonal violence such as combat veterans, populations affected by genocide, survivors of rape, or those previously held 3. Recommend lifestyle modifications and captive, PTSD prevalence estimates are estimated to rise drug treatment options for post-traumatic to 25-50 percent. With the increased availability of graphic videos and images available via media outlets and the 4. Compare the advantages and disadvantages internet, there is a concern of a potential rise in the preva- for the various treatment options used in post- lence of PTSD in the population of viewers of this material, but the expected prevalence of PTSD development after 5. Design appropriate education for patients on witnessing an event is thought to be lower than if actually the rationale, appropriate use and adverse confronted with the event. In addition to developing PTSD, effects of medications used for post-traumatic those exposed to traumatic events are at increased risk for stress disorder. major depression, panic disorder, generalized anxiety dis-order, substance abuse, hypertension, asthma and chronic Upon successful completion of this article, the pharmacy technician should be able to:1. Explain the pathophysiology of post-traumatic PATHOPHYSIOLOGY
A number of biochemical processes are thought to be 2. Describe the risk factors and symptoms of involved in the development and throughout the course of PTSD. The amygdala and hippocampus as well as the 3. Discuss lifestyle modifications and com- neurotransmitters serotonin, norepinephrine (NE) and do- pamine are commonly cited. The amygdala is the portion of the brain responsible for fear response and is thought 4. Identify patients at risk for, or exhibiting signs to signal the hippocampus which appears to assist in the of, post-traumatic stress disorder and refer development of memories. Imaging studies of PTSD pa- patients to the pharmacist for further assess- tients have demonstrated altered activity in both areas. It is thought that at the time of the trauma a number of factors (such as previous traumas, ethnicity, support immediately Post-traumatic stress disorder (PTSD) is an following trauma) may influence the body’s response. If the anxiety disorder resulting from either the direct body is unable to contain the biological stress, this may involvement with or the witnessing of a traumatic progress to the development of symptoms including intru- November 2013 | america’s PHARMACIST 39
sive recollection, re-experiencing, avoidance, numbness will not respond to pharmacotherapy alone. and hyperarousal. Changes in the body’s initial response Engagement of families and supportive indi- to the trauma may be due to lower cortisol levels which viduals is also recommended as involving them may lead to greater availability of NE. In general, patients in treatment may assist in achieving optimal with PTSD tend to have higher levels of NE in their central outcomes. Once the patient’s symptoms are nervous systems (CNS) and to a lesser extent in the pe- controlled, treatment should focus on attempt- riphery. In addition to elevations in NE, there appear to be ing to work with the patient’s ability to cope with alterations in the signaling of a number of CNS pathways situations. This may assist in preventing future that result in the symptoms experienced in PTSD that have relapses or exacerbations from other poten- not clearly been delineated at this time.
tially traumatic events so the patient is able to maintain a sense of safety and trust. To prevent CLINICAL PRESENTATION/DIAGNOSIS
relapse, medication therapy often needs to be The diagnosis of PTSD is made if an individual has been personally exposed to or witnessed a traumatic event. This event inspires fear, hopelessness, or horror NON-PHARMACOLOGIC THERAPIES/
in the individual. Following the trauma, the individual of- PSYCHOTHERAPY
ten begins to re-experience the event and may attempt There are a number of different approaches to avoid people or places associated with the event. recommended for the treatment of PTSD. Cog- Some individuals may become desensitized or numb nitive behavioral therapy is recommended to to their surroundings while still experiencing increased commence two to three weeks following expo- symptoms of hyperarousal. Episodes are considered sure to the trauma to prevent the development acute if the symptoms last for more than one month but of PTSD or to accelerate recovery. This therapy less than three months, while episodes are considered focuses on desensitizing the patient to trauma- chronic if the symptoms last more than three months. A related triggers. Eye movement desensitization third subset is delayed-onset PTSD, where six months and reprocessing (EMDR) requires the patient or more have passed following the traumatic experi- to recall traumatic material while simultane- ence before the onset of symptoms. Symptoms may ously focusing on an external stimulus.
be present in patients of any age and the duration of The efficacy of EMDR is thought to be simi- the illness varies. Approximately half of patients have lar to that of other non-pharmacologic options. complete recovery within three months, but symptom Individual and group therapy focus on educating reactivation may occur with exposure to reminders of patients about the condition as well as restruc- turing the patient’s thoughts and automatic responses to thoughts, images or experiences. DESIRED GOALS/OUTCOMES
Learning a variety of coping skills may assist Goals for the treatment of PTSD involve the resolution of in managing anxiety during these experiences. all PTSD symptoms experienced by the patient as well as Support groups are also available for family and any co-morbid conditions such as other anxiety disor- friends to provide education and skills to help ders, depression or substance abuse. To achieve this these important individuals play an active role in goal, combination psychotherapy and pharmacotherapy facilitating the recovery of their loved one. Not are often utilized as approximately 40 percent of patients all of the non-pharmacologic therapies are ap- Persistent and intrusive recollections, dreams, or flashbacks of the event Avoiding thoughts, feelings, activities, or people associated with the trauma; reduced interest in significant activities; restricted emotional range; difficulty conceptualizing a long-lasting life Difficulty falling or staying asleep, nightmares, irritability, impaired concentration, hypervigilance, or 40 america’s PHARMACIST | November 2013
propriate for all PTSD patients. Similar to other antidepressant response or for use in treatment-refractory mental illnesses, treatment should be tailored to patients with varying degrees of success. Antidepressant the needs of the individual, including the recog- doses for sertraline and paroxetine are similar to dosing nition that these needs often change over time.
for other indications and should be titrated from a start-ing dose to that which is clinically effective and tolerated. PHARMACOLOGIC TREATMENT
Sertraline dose should start at 50 mg once daily, up to 200 mg daily and paroxetine dose should start at 20 mg once Currently, paroxetine and sertraline are the only daily, up to 60 mg. The same approach to dosing could be two medications approved for PTSD by the Food applied to off-label use of other drugs as illustrated in the and Drug Administration (FDA). Selective sero- following table. Patients responding to pharmacotherapy tonin reuptake inhibitors (SSRIs) and serotonin should continue treatment for at least one year.
norepinephrine reuptake inhibitors (SNRIs) are All antidepressants carry a black box warning for first-line pharmacotherapeutic options for the suicidal thinking and behavior (http://www.fda.gov/ treatment of PTSD due to their safety, efficacy, Drugs/DrugSafety/InformationbyDrugClass/ucm096273.
and tolerability. Nevertheless, antidepressants htm) in children, adolescents and young adults (up to have not consistently demonstrated benefit age 24 years). Families and friends should be engaged across all patient types (such as civilian versus to communicate signs of suicidal thinking and behavior combat-related PTSD) and symptom clusters (such as re-experiencing, avoiding/numbing, and hyperarousal). Various medications have been SELECTIVE SEROTONIN REUPTAKE INHIBITORS
investigated as adjunctive therapy to enhance SSRIs are first-line options for the treatment of PTSD. They Common Medications for the Treatment of PTSDGeneric Name a Paroxetine and sertraline are FDA-approved for the treatment of PTSD.
b The dosage should be increased according to the patient’s response and tolerability. Usual serum concentrations range from 50- c Lamotrigine dosing is influenced by concomitant medications. Initiate lamotrigine at half the regular starting dose (i.e., 25mg every other day) with concurrent divalproex therapy or twice the regular starting dose (i.e., 50mg once daily) with concurrent metabolic November 2013 | america’s PHARMACIST 41
are considered effective treatment for all three PTSD symp- pressants, such as paroxetine, than those with tom clusters: re-experiencing, avoidance/numbing, and longer half-lives and active metabolites, such as hyperarousal. Furthermore, they also treat co-morbidities that fluoxetine and its active metabolite, norfluoxetine.
frequently accompany PTSD, including depression, suicidal- The FDA has approved six SSRIs: citalopram ity, and impulsivity. Finally, SSRIs have a favorable side effect (Celexa), escitalopram (Lexapro), fluoxetine (Pro-profile relative to many other psychotropic medications.
zac), fluvoxamine (Luvox), paroxetine (Paxil), and SSRIs are specific for inhibiting the presynaptic reup- sertraline (Zoloft). SSRIs are FDA-approved for take of serotonin via blockade of the serotonin transporter a number of conditions, including major depres- pump. They display relatively weak effects on the reuptake sive disorder, generalized anxiety disorder, panic of other neurotransmitters, notably norepinephrine and disorder, obsessive-compulsive disorder, and dopamine. SSRIs also have low affinity for histaminergic, bulimia nervosa. While sertraline and paroxetine muscarinic, and  adrenergic receptors; therefore, they are are the only medications approved for PTSD, considerably more tolerable than the tricyclic antidepres- many clinicians regard all SSRIs as having similar sants (TCAs). Despite similarities across SSRIs, individual efficacy in its treatment. Unfortunately, head-to- agents vary with regard to other properties, such as phar- head trials among SSRIs for PTSD are lacking. macokinetic parameters and side effect profiles.
Sertraline, paroxetine, and fluoxetine currently Side effects are generally mild and more tolerable have the most evidence for use in PTSD.
than many other psychotropic medications. Common side effects include gastrointestinal disturbances (nausea, diar- medications for the treatment of PTSD. Two ran- rhea), sexual dysfunction, headache, insomnia, somno- domized, placebo-controlled, 12-week trials in lence, restlessness and anxiety. While side effects such as civilian-related PTSD found sertraline superior to gastrointestinal disturbances are transient, resolving within placebo. The first trial evaluated 187 outpatients the first few days to weeks of therapy, sexual dysfunction with sertraline doses ranging from 50 to 200 mg/ may often persist. It has been estimated that upwards of day. Compared to placebo, sertraline signifi- 60 percent of patients report signs of treatment-related cantly decreased the Clinician-Administered sexual dysfunction during SSRI therapy, including symp- PTSD Scale (CAPS) total score [-33.0 vs -23.2 toms of decreased libido, erectile dysfunction, and de- (p=0.02)] and was well tolerated. Response rate layed or absent orgasm or ejaculation.
was defined as a greater than 30 percent reduc- Other potential side effects include hyponatremia, tion in CAPS total score and a Clinical Global abnormal bleeding, and discontinuation symptoms. The Impression - Improvement (CGI-I) score of 1 or mechanism of SSRI-induced hyponatremia has not been 2. Overall, patients receiving sertraline had a fully elucidated; however, risk factors for its development 53 percent response rate versus 32 percent for include older age, female gender, concurrent diuretic use, placebo. The second trial investigated 208 out- and a lower serum sodium concentration at baseline. patients with sertraline doses ranging from 50 to Abnormal bleeding has been observed with SSRI therapy. 200 mg/day. Once again, sertraline significantly It has been suggested that the risk of abnormal bleeding improved efficacy measures versus placebo, secondary to SSRIs is caused by the inhibition of serotonin notably the CAPS total score [-33.0 vs -26.2 uptake into platelets. Gastrointestinal bleeding is most (p=0.04)]. Criteria for response were defined often observed; nevertheless, the overall risk appears low. similarly to the previous trial. Overall, patients The risk appears to be increased with concurrent antico- receiving sertraline had a 60 percent response agulant, antiplatelet, or nonsteroidal anti-inflammatory drug rate, versus 38 percent for placebo. In contrast use. Discontinuation syndrome is manifested by the abrupt to the previous studies, a more recent 12-week discontinuation of therapy. Flu-like symptoms, insomnia, trial evaluated 169 outpatients with predomi- nausea, dizziness, anxiety, and sensory disturbances (par- nantly combat-related PTSD. Sertraline failed to esthesias) are common features. Discontinuation syndrome separate from placebo in primary or secondary occurs more commonly with the shorter half-life antide- endpoints. Finally, sertraline was evaluated in 42 america’s PHARMACIST | November 2013
a 28-week trial examining its effects on relapse cut-off score of 1 was utilized, the response rate differed prevention. Patients completed both an initial significantly, with 59 percent for fluoxetine and 19 percent 12-week and subsequent 24-week treatment for placebo. An internationally conducted randomized, phase and were considered sertraline treatment placebo-controlled, 12-week trial consisted of 301 combat responders. A total of 96 patients then entered and civilian-related PTSD patients. Fluoxetine was dosed a 28-week, double-blind study and were ran- 20 to 80 mg/day. The primary efficacy measure was the domized to continue sertraline therapy or initiate change in Treatment Outcome PTSD rating scale (TOP-8) placebo. Continued treatment with sertraline total score. Fluoxetine significantly improved the TOP-8 total resulted in significantly fewer patients relapsing, score versus placebo as well as significantly improving the with 5.3 percent versus 26.1 percent for placebo.
CAPS total score [-34.6 vs -26.8 (p=0.021)]. Response Paroxetine is also FDA-approved for the treat- rates were 59.9 percent for fluoxetine and 43.8 percent for ment of PTSD. Paroxetine was shown to be effec- placebo. Fluoxetine has also been studied for relapse pre- tive in two placebo-controlled, 12-week trials. The vention. A placebo-controlled discontinuation study evalu- first trial evaluated 307 patients with paroxetine ated 57 patients. Patients enrolled in the study received doses ranging from 20 to 50 mg/day. The primary open-label fluoxetine treatment for six months. The patients outcome was change in CAPS total score as well were then randomized to receive fluoxetine 10 to 60 mg/day as the proportion of responders on the CGI-I. The or placebo for an additional six months in a double-blinded average dose of paroxetine was 27.6 ± 6.72 mg/ fashion. Utilizing CGI-I scores, placebo had a significantly day. Compared to placebo, paroxetine significant- higher relapse rate of 50 percent versus fluoxetine at 22.2 ly decreased the CAPS total score [-35.5 vs -24.7 percent. Furthermore, the time to relapse was significantly (p=<0.001)]. The response rate was significantly greater for paroxetine than placebo at approxi- A second study examining relapse prevention selected mately 60 percent versus 40 percent, respectively. patients responding to 12 weeks of acute treatment. Follow-The second trial evaluated 551 patients random- ing acute treatment, a total of 131 patient responders were ized to receive either paroxetine 20 mg/day, 40 randomized in a double-blind fashion to receive either fluox- mg/day, or placebo. Paroxetine 20 mg/day, 40 etine or placebo for an additional 24 weeks. The average mg/day, and placebo decreased the CAPS total dose by study endpoint was 53 mg/day. While fluoxetine score by -39.6, -37.9, and -25.3, respectively. failed to separate from placebo with regard to the CAPS to- Improvement was significantly greater for both ac- tal score, fluoxetine was able to significantly prevent relapse tive treatments versus placebo. The percentage of versus placebo. Other trials have failed to show any benefit patients achieving response was 62 percent with with fluoxetine therapy. A placebo-controlled, 12-week trial paroxetine 20 mg/day, 54 percent with paroxetine evaluated fixed doses of fluoxetine 20 and 40 mg/day. The 40 mg/day, and 37 percent with placebo.
trial included predominately women and utilized the TOP- While fluoxetine is not FDA-approved for 8 as the primary outcome measure. Fluoxetine failed to the treatment of PTSD, literature exists support- produce significant changes in the TOP-8 total score or in ing its use. An early trial of 64 patients evalu- response rates. Similarly, fluoxetine 20 mg/day and 40 mg/ ated fluoxetine versus placebo. Despite its short day failed to separate from placebo with regard to the CAPS five-week duration, fluoxetine significantly de- total score with changes of -42.9, -42.8, and -36.6, respec- creased the CAPS total score. A randomized, tively. A possible explanation for the lack of benefit may placebo-controlled, 12-week trial of civilians involve the dosing of fluoxetine with higher overall doses examined fluoxetine in doses up to 60 mg/day. potentially needed to produce the desired effects in PTSD.
Of the 53 patients, 91 percent were women. The The remaining SSRIs have also been investigated for Duke Global Rating for PTSD was the primary the treatment of PTSD to varying degrees. Citalopram, outcome measure. When a Duke cut-off score of recently scrutinized by the FDA for dose-dependent QT 1 or 2 was utilized to define response, differences prolongation concerns, has favorable data from open-label were not statistically significant. When a Duke trials. A double-blind comparison of citalopram, sertraline, November 2013 | america’s PHARMACIST 43
and placebo supported a beneficial class effect of SSRIs combat-related PTSD were randomized to either on PTSD. Escitalopram, the active S-enantiomer of race- venlafaxine extended-release ranging from 37.5 mic citalopram, has only preliminary open-label trial data to 300 mg/day, sertraline 25 to 200 mg/day, or suggesting efficacy. Fluvoxamine, predominantly utilized in placebo. The primary outcome measure was obsessive-compulsive disorder, has demonstrated ben- change in CAPS score. Average doses were 225 eficial effects in PTSD, as well. Nevertheless, paroxetine, mg and 151 mg for venlafaxine extended-release sertraline, and fluoxetine continue to be the most rigorously and sertraline, respectively. Changes in CAPS evaluated SSRIs for the treatment of PTSD.
scores were -41.5, -39.4, and -34.2 for venlafax-ine extended-release, sertraline, and placebo, SEROTONIN NOREPINEPHRINE
respectively. Differences between venlafaxine REUPTAKE INHIBITORS
extended-release and placebo were statistically There are currently four FDA-approved SNRIs available: significant for the primary outcome; however, dif- venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine ferences between venlafaxine extended-release (Cymbalta), and milnacipran (Savella). SNRIs inhibit the and sertraline were not statistically significant.
presynaptic reuptake of serotonin and norepinephrine to varying degrees. Venlafaxine, for example, inhibits the reup- MISCELLANEOUS ANTIDEPRESSANTS
take of serotonin at low doses, whereas higher doses are A number of other antidepressants have been needed to additionally inhibit the reuptake of norepinephrine. evaluated for the treatment of PTSD. Bupropion Desvenlafaxine is the primary active metabolite of venla- (Wellbutrin) inhibits the presynaptic reuptake of faxine. Duloxetine is unique in that it is FDA-approved for a dopamine and norepinephrine. Common side ef- number of pain indications, including diabetic neuropathy, fects include insomnia, dry mouth, nausea, and fibromyalgia, and chronic musculoskeletal pain. Milnacipran, weight loss. Contraindications include patients the newest SNRI available, is currently only FDA-approved with seizure disorders, a history of anorexia or for the management of fibromyalgia. Side effects vary slightly bulimia nervosa, and the abrupt discontinuation among the SNRIs; however, a notable difference from SSRIs of alcohol or sedatives. Ask patients or caregiv- includes dose-dependent increases in blood pressure. ers about seizure history if the patient is known Blood pressure should be monitored regularly throughout to have suffered a head trauma. Overall, bu- therapy. Similar to paroxetine, venlafaxine is prone to causing propion was found to be ineffective for PTSD in a discontinuation syndrome. A gradual taper is necessary two controlled trials. Mirtazapine (Remeron) has when discontinuing, and patients should be counseled on multiple receptor effects, including  receptor the symptoms of the discontinuation syndrome.
antagonism, 5-hydroxytryptamine (5-HT) recep- Currently, venlafaxine is the only SNRI with published tor antagonism, specifically at 5-HT and 5-HT controlled trials in PTSD. A randomized, placebo-con- receptors, and histamine receptor antagonism. trolled, six-month trial investigated venlafaxine extended- Common side effects include sedation and release. A total of 329 patients with both civilian and weight gain. Interestingly, the dose of mirtazap- combat-related PTSD were evaluated. The primary end ine and associated sedation are inversely pro- point was change in total CAPS score. Venlafaxine was portional. In a small trial of 29 patients, mirtazap- dosed 37.5 to 300 mg/day with an average daily dose ine was associated with a significantly greater of 221.5 mg/day. Overall, venlafaxine significantly im- rate of global response than placebo. Vilazodo- proved CAPS total score versus placebo [-51.7 vs -43.9 ne (Viibryd), the newest available antidepressant, (p=0.006)]. Remission rates were significantly greater has not been studied in the treatment of PTSD.
with venlafaxine than placebo with 50.9 percent and 37.5 percent, respectively. Blood pressure changes did not sig- scribed; however, an evidence base supports nificantly differ between groups. A second trial compared its use for the treatment of PTSD. Nefazodone venlafaxine extended-release to sertraline and placebo for inhibits the reuptake of serotonin and norepi- twelve weeks. A total of 538 patients with either civilian or nephrine and antagonizes the 5-HT receptor. 44 america’s PHARMACIST | November 2013
Sedation, orthostatic hypotension, and blurred BENZODIAZEPINES
vision are common side effects. The widespread Benzodiazepines enhance the activity of -aminobutyric use of nefazodone has been limited by warn- acid (GABA), the major inhibitory neurotransmitter of the ings of hepatotoxicity. The estimated rate of CNS, and possess anxiolytic, sedative, anticonvulsant, nefazodone-induced liver failure in the United and myorelaxant properties. While benzodiazepines are States is 1 per 250,000 to 300,000 patient-years frequently utilized in other anxiety disorders, their benefits of nefazodone treatment. The majority of cases in PTSD appear limited. Benzodiazepines may alleviate occurred after at least four weeks of treatment, symptoms of anxiety or insomnia; however, they have not with only a few occurring beyond six months. been shown to improve the core symptoms of PTSD or Nevertheless, routine liver function testing is ad- prevent its occurrence. Another disadvantage includes the vised throughout therapy. Drug interactions are potential for abuse, particularly in a population where sub- also concerning as nefazodone strongly inhibits stance abuse may be common. Overall, benzodiazepines cytochrome P450 (CYP) 3A4. Interactions with should be avoided or minimized as they are ineffective for several common medications such as droneda- the treatment or secondary prevention of PTSD, harbor rone, simvastatin, and tamsulosin often require concerns of tolerance and dependence, and potentially the prompt intervention of the pharmacist.
worsen symptoms upon their discontinuation.
A crossover trial of 16 patients examined the effects suggest nefazodone is an efficacious treatment of up to 6 mg/day of alprazolam (Xanax) versus placebo for PTSD. A randomized, placebo-controlled, 12- for five weeks. Three patients in each group left the study week trial in a mixed civilian and veteran popula- citing treatment as ineffective; therefore, 10 patients tion of 41 patients also demonstrated its effective- completed the study. After the initial five weeks in either ness. Nefazodone was dosed up to 600 mg/day treatment arm, patients were switched during a two-week with an average dose of 435 mg/day. Compared interim phase and treated with the opposite treatment for to placebo, nefazodone significantly decreased an additional five weeks. Among the various rating scales the CAPS total score [-19.1 vs -13.5 (p=0.04)]. utilized, alprazolam only demonstrated statistically signifi- Response rate was defined as  30 percent cant improvement on the Hamilton Rating Scale for Anxiety improvement in the CAPS total score. While there (HAM-A) while failing to separate from placebo on any was a significant difference in responders at week other measures. A small, randomized, single-blind, cross-four, by week 12 the difference in responders was over trial of six patients investigated the effects of clonaz- not significant with 47 percent in the nefazodone epam (Klonopin) on sleep in combat-related PTSD. Patients group, and 42 percent in the placebo group. A were given clonazepam 1 mg at bedtime for one week, head-to-head, 12-week trial of 37 patients com- followed by 2 mg at bedtime for one-week. After the initial pared nefazodone and sertraline therapy. While two weeks, patients underwent a one week washout period both treatments produced significant changes on before switching to the alternate treatment for two weeks. each outcome measure, no significant difference Overall, clonazepam failed to separate from placebo and was found between agents. Despite the small was mostly ineffective at improving sleep or nightmares.
sample size, nefazodone was deemed as effec- Benzodiazepine therapy has also been evaluated tive as sertraline for the treatment of PTSD.
immediately following trauma for the prevention of PTSD. The TCAs and monoamine oxidase inhibitors Patients were evaluated within two days of trauma and, (MAOIs) are not first-line pharmacotherapeutic following initial assessments, were screened by a research agents for the treatment of PTSD. While each psychiatrist for appropriateness of benzodiazepine therapy. drug class has been evaluated in PTSD, food Of 162 patients evaluated, 13 were initiated on benzodi- and drug interactions and narrow therapeutic azepine therapy with either alprazolam or clonazepam. index concerns have relegated these agents as The 13 patients were then matched based on gender treatment options only after trials of newer anti- and symptom severity in the first week with an untreated control group. At both the one and six month follow-ups, November 2013 | america’s PHARMACIST 45
the benzodiazepine group failed to show a difference from either prazosin or placebo for three weeks, fol- the control group in mitigating the development of PTSD. lowed by a one-week washout period before In fact, nine patients (69 percent) in the benzodiazepine switching to the opposite treatment. Prazosin was group and only two (15 percent) in the control group met initiated at 1 mg at bedtime with an average dose of approximately 3.1 mg. Prazosin increased total sleep time [374 ± 86 minutes versus 280 ± 105 SYMPATHOLYTICS
minutes (p<0.01)] and significantly decreased Excessive norepinephrine activity in the CNS has been implicated in the underlying pathophysiology of PTSD. Medications that blunt noradrenergic activity have been prazosin and quetiapine (Seroquel) therapy over investigated in its treatment. Prazosin (Minipress), an  a six-month period. A total of 237 patients were adrenergic receptor antagonist, is utilized as an adjunct to included with 62 receiving prazosin and 175 re-antidepressant therapy. Prazosin, administered at bed- ceiving quetiapine. Authors relied on chart docu- time, alleviates symptoms of hyperarousal such as sleep mentation of symptom improvement. Short-term disturbances and nightmares. Dosages are initiated low effectiveness was similar between groups with and increased gradually to minimize orthostatic hypoten- symptom improvement noted in 61.3 percent of sion. Several retrospective chart reviews and open-label prazosin patients and 61.7 percent of quetiapine trials of civilian and combat-related PTSD have shown patients. Conversely, significantly more patients continued prazosin versus quetiapine to study Two placebo-controlled trials in combat-related PTSD end date, with 48.4 percent and 24 percent, and one in civilian-related PTSD support the use of prazo- respectively. In addition, significantly more pa- sin as adjunctive therapy. The first combat-related PTSD tients discontinued quetiapine secondary to the trial evaluated 10 patients with trauma-related nightmares. side effects, including sedation and cardiometa- Five patients received either prazosin or placebo for an initial nine weeks. After a two-week washout period, the patients were switched to the opposite treatment for an SECOND GENERATION ANTIPSYCHOTICS
additional nine weeks. The dose of prazosin was gradually Second generation antipsychotics, also known titrated to minimize orthostatic hypotension, and the aver- as atypical antipsychotics, are increasingly age dose was 9.5 mg at bedtime. Prazosin was superior utilized as adjunctive medications for treatment- to placebo on all three primary outcome measures and refractory PTSD. Unlike first generation antipsy- was well tolerated. A second combat-related PTSD trial chotics, such as haloperidol, which predomi- investigated 34 patients randomized to receive prazosin nately exert effects via dopamine antagonism at or placebo for eight weeks. Prazosin was initiated at 1 the D receptor, second generation antipsychot- mg to minimize orthostatic hypotension and titrated to a ics are both D and 5-HT receptor antagonists. maximum of 15 mg at bedtime. The average dose was While pharmacologic differences afford the approximately 13 mg. By week eight, prazosin significantly second generation antipsychotics lower rates of differed from placebo on all three primary outcome mea- extrapyramidal symptoms, clinicians must con- sures assessing nightmares. Recurrent distressing dreams tinue to monitor for tardive dyskinesia with these decreased more than 50 percent, versus 15 percent for agents. FDA has issued a black box warning prazosin and placebo, respectively. Side effects were more against using these medications in the elderly common with prazosin therapy, with transient orthostatic with dementia-related psychosis. Second gen- hypotension, nasal or sinus congestion, and headache eration antipsychotics also have a propensity for being the most common. Differences in blood pressure causing cardiometabolic disturbances, including changes did not differ significantly between groups. Finally, weight gain, hyperlipidemia, and diabetes mel-a randomized, placebo-controlled, crossover trial examined litus. Current guidelines for monitoring meta-13 patients with civilian-related PTSD. Patients received bolic parameters recommend that weight, waist 46 america’s PHARMACIST | November 2013
circumference, blood pressure, fasting plasma small randomized, placebo-controlled trial of 15 patients. lipids, and glucose are monitored throughout A slow dose titration was required to minimize the risk therapy. Risperidone (Risperdal), olanzapine of rash. Two patients in both the lamotrigine group (20 (Zyprexa), and quetiapine have accumulated the percent) and placebo group (50 percent) developed most data as adjunctive therapies for PTSD.
rashes and dropped out of the study. Overall, lamotrigine Risperidone is the most extensively studied was more effective than placebo; however, the small second generation antipsychotic with a total sample size may limit the generalizability of the results. of seven placebo-controlled trials and several Topiramate (Topamax) has been studied in open-label open-label trials. Overall, results appear to be trials as well as one placebo-controlled trial in civilian- mixed. Risperidone has significantly improved related PTSD and two placebo-controlled trials in the CAPS total score versus placebo; however, combat-related PTSD. Data with topiramate are limited at small sample sizes and other limitations often this time, and results have been mixed. Further study is affect the generalizability of these study results. needed for levetiracetam (Keppra) after a retrospective The most recent risperidone trial evaluated its analysis of 23 partial or nonresponders to antidepressant use as an adjunct to antidepressant therapy. therapy suggested benefit. Finally, tiagabine (Gabitril), a This six-month, randomized, placebo-controlled GABA reuptake inhibitor, failed to separate from placebo trial consisted of 247 combat-related PTSD in a large randomized, controlled trial.
patients. Doses of risperidone up to 4 mg/day
were utilized. At the end of 24 weeks, risperidone CONCLUSIONS
failed to separate from placebo on the primary
PTSD is an anxiety disorder resulting from direct exposure outcome measure of CAPS total score [-16.3 to or witnessing of a traumatic event. Core symptoms of versus -12.5 (p=0.11)]. Furthermore, the rate of PTSD are divided into three symptom clusters: re-experi- patients achieving remission did not significantly encing, avoidance/numbing, and hyperarousal. Non-phar- differ between risperidone and placebo at 5 macologic and pharmacologic treatment strategies have percent and 4 percent, respectively.
been investigated in the treatment of PTSD. With regard to pharmacologic treatment, the SSRIs and venlafaxine are ANTICONVULSANTS
first-line pharmacotherapeutic options secondary to their Anticonvulsants have also been evaluated safety, efficacy, and tolerability. Prazosin appears to be an effective adjunct for sleep disturbances and nightmares. pharmacotherapy. Case reports and open-label Anticonvulsants and second generation antipsychotics trials have suggested benefit with divalproex have mixed results as adjuncts to antidepressant therapy. (Depakote); however, two recent randomized, Finally, benzodiazepines are not recommended second- placebo-controlled trials demonstrated a lack ary to lack to efficacy in treating core symptoms as well as of clear benefit. An eight-week trial consisting of potentially harmful effects. It is important to tailor treatment 85 patients with combat-related PTSD examined to the needs of each individual patient. change in the CAPS hyperarousal subscale. Doses of divalproex averaged 2,309 ± 507 mg/day and serum levels averaged 82 ± 30 mg/L. Chris Paxos, PharmD, BCPP, CGP, is an assistant professor No significant differences were found between of pharmacy practice at Northeast Ohio Medical University, divalproex and placebo on the primary outcome and the pharmacotherapy specialist in psychiatric medicine at measure. Another trial of divalproex evaluated Akron General Medical Center in Akron, Ohio. 29 patients with predominantly combat-related PTSD. Divalproex was not superior to placebo, Sara E. Dugan, PharmD, BCPP, is an associate professor of and the placebo group managed to significantly pharmacy practice at Northeast Ohio Medical University and improve the CAPS avoiding/numbing subscale. a clinical pharmacist with Klein's Pharmacy at Community Lamotrigine (Lamictal) was evaluated in a Support Services, Inc., in Akron, Ohio.
November 2013 | america’s PHARMACIST 47
Post-Traumatic Stress Disorder Current Approach to Treatment
Nov. 1, 2013 (expires Nov. 1, 2016) • Activity Type: Knowledge-based
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Select the correct answer.
3. Which of the following would be a re-experi-
encing symptom in a rape victim with PTSD?
1. Which of the following non-pharmacologic treatment
a. Recurrent thoughts of gun battles making her options is recommended in the two to three weeks fol- lowing the trauma to minimize or possibly prevent the b. Hallucinations of a plane crash where she c. Feelings of helplessness whenever she hears b. Eye movement desensitization and reprocessing d. Vivid dreams of the attack that wake her up 4. Imaging studies have shown that which of
2. The use of non-pharmacologic therapy in the treatment the following brain structures appear to be
of PTSD can best be described as:
a. The mainstay, first-line treatment for all PTSD patients b. Essential methods of therapy that are primarily respon- c. A collection of diverse treatments that are used in com- d. A necessary tool that assists the patient until the medi- 5. What neurotransmitter is clearly involved in
the development of PTSD?a. Corticotropin releasing factorb. Dopaminec. Norepinephrined. Serotonin 48 america’s PHARMACIST | November 2013
6. The role of cortisol in PTSD is best described 9. M.H. is a domestic abuse survivor. Now in a healthy
as being:
marriage with a 2-year-old child, she experiences panic a. Lower than expected at the time of the and fear when the child hits her while throwing a tantrum. b. Higher than expected at the time of the d. No diagnosis of PTSD can be made more than six d. Not involved in the development of PTSD 10. All of the following are symptom clusters of PTSD,
7. Which of the following is true regarding the
a. Complete control of re-experiencing symp- b. Long-term medication use is often needed to d. Re-experiencing c. Psychotherapy is superior to medication in 11. Antidepressants are considered first-line pharmaco-
logic treatment options because they alleviate the follow- d. Treatment is patient specific and no family 8. R.S. is a scuba diver who was severely injured c. Re-experiencing
when a boater did not recognize his diver down
flag and drove over him. Which of the following is true of acute PTSD: 12. Which of the following are the only FDA-approved
a. It occurs only at the time of the trauma.
b. It lasts from one to three months.
d. It is only diagnosed when the victim or wit- 13. Which of the following SSRIs is most likely to cause
discontinuation syndrome with missed doses?
a. Escitalopram
b. Fluoxetine
c. Paroxetine
d. Sertraline
November 2013 | america’s PHARMACIST 49
14. Which of the following medications inhibits the reup-
18. All of the following are required monitoring
take of serotonin and norepinephrine into presynaptic parameters for second generation antipsychot- 15. M. J. suffered a traumatic brain injury and now experi-
19. Risk factors for the development of SSRI-
ences seizures. Which of the following medications is induced hyponatremia include all of the follow- contraindicated in patients with a seizure disorder? 16. Which of the following statements regarding benzodi-
20. Which of the following antidepressants is a
azepine therapy in the treatment of PTSD is TRUE? strong inhibitor of CYP3A4, thereby contraindi- a. Benzodiazepines are useful for treating co-morbid cating its use with CYP3A4 substrates such as dronedarone, simvastatin, and tamsulosin.
b. Benzodiazepines do not produce tolerance and de- c. Benzodiazepines have not been shown to improve d. Benzodiazepines prevent the occurrence of PTSD fol- 17. Adjunctive prazosin therapy is most helpful for which
of the following symptoms:
a. Flashbacks
b. Difficulty concentrating
c. Impulsivity
d. Nightmares
50 america’s PHARMACIST | November 2013

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