Clinician's Guide to Medications for PTSD
Matt Jeffereys, M.D.
Overview:
Posttraumatic Stress Disorder (PTSD) has biological, psychological, and social components. Medications can be used in treatment to address the biological basis for PTSD symptoms and co-morbid Axis I diagnoses. Medications may benefit psychological and social symptoms as well. While studies suggest that cognitive behavioral therapies such as prolonged exposure (PE) and cognitive processing therapy (CPT) have greater effects in improving PTSD symptoms than medications, some people may prefer medications or may benefit from receiving a medication in addition to psychotherapy.
Placebo controlled double blind randomized controlled trials are the gold standard for pharmacotherapy. Less strongly supported evidence includes open trials and case reports. It is important for the clinician to question the level of evidence supporting the medications prescribed in PTSD treatment. There are a variety of factors influencing prescribing including marketing, patient preferences, and clinical custom which sometimes are inconsistent with the evidence base.
The evidence base is strongest for the selective serotonin reuptake inhibitors (SSRI's). The only two FDA approved medications for the treatment of PTSD are sertraline (Zoloft) and paroxetine (Paxil) (1, 2). All other medication uses are off label, though there are differing levels of evidence supporting their use. There are a number of biological changes which have been associated with PTSD, and medications can be used to modify the resultant PTSD symptoms. Veterans whose PTSD symptoms have been present for many years pose a special challenge. Studies indicate they are more refractory to the beneficial effects of medications for PTSD symptoms (3).
What core PTSD symptoms are we trying to treat?
The three main PTSD symptom clusters are listed below:
Re-experiencing:
Examples include nightmares, unwanted thoughts of the traumatic events, and flashbacks.
Avoidance:
Examples include avoiding triggers for traumatic memories including places, conversations, or other reminders. The avoidance may generalize to other previously enjoyable activities.
Hyperarousal:
Examples include sleep problems, concentration problems, irritability, increased startle response, and hypervigilance.
What are some of the biological disturbances found in PTSD?
Some of the main biological disturbances in PTSD can be conceptualized as dysregulation of the naturally occurring stress hormones in the body and increased sensitivity of the anxiety circuits in the brain. Yehuda and others have found that patients with PTSD have hypersensitivity of the hypothalamic-pituitary-adrenal axis (HPA) as compared to patients without PTSD (4). Patients have a much greater variation in their levels of adrenocorticoids than patients without PTSD. Other researchers have found differences in the anatomy of the fear center of the brain between patients with PTSD and those without. It is not known for certain whether these changes were present before the traumatic event and predisposed the person to developing PTSD or whether these changes were the result of the PTSD. One way to think of this is the fear circuitry no longer being integrated with the executive centers of the brain located in the prefrontal cortex. Even minor stresses may then set off the "fight or flight" response in patients with PTSD which leads to increased heart rate, sweating, rapid breathing, tremors, and other symptoms of hyperarousal listed above.
How do medications help regulate these responses?
The medications prescribed for treating PTSD symptoms act upon neurotransmitters related to the fear and anxiety circuitry of the brain including serotonin, norepinephrine, GABA, and dopamine among many others. There is great interest in developing newer more specific agents than are currently available to target the PTSD symptoms described earlier while minimizing potential side effects of medications. Studies show that a number of medications are helpful in minimizing the three symptom clusters of PTSD. Most of the time, medications do not entirely eliminate symptoms but provide a symptom reduction and are best used in conjunction with an ongoing program of trauma specific psychotherapy for patients such as PE or CPT.
How do we measure the effects of treatment?
There are a number of self-rating scales and structured clinical interviews to monitor the effects of treatment. Two examples include the Post-Traumatic Stress Disorders Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS). The PCL military or civilian version is an example of a patient self-rating form without stressor information while the CAPS is an example of a structured clinical interview including stressor information. There is literature supportive of a strong correlation between the two measures, and the PCL has the advantage of being quick and easy to administer. Both the PCL and the CAPS will provide a quantitative measure of the patient's PTSD symptoms and response to treatment over time that will enhance the clinical assessment and interview with the patient.
What is the evidence base for the specific groups of medications used for PTSD treatment?
Selective Serotonin Reuptake Inhibitors (SSRI's). These medications are the only FDA approved medications for PTSD . SSRIs primarily affect the neurotransmitter serotonin which is important in regulating mood, anxiety, appetite, and sleep and other bodily functions. This class of medication has the strongest empirical evidence with well designed randomized controlled trials (RCT's) and is the preferred initial class of medications used in PTSD treatment (1, 2). Exceptions may occur for patients based upon their individual histories of side effects, response, and comorbidities. An example of an exception would be a PTSD patient with comorbid Bipolar Disorder. In this patient, there is a risk of precipitating a manic episode with the SSRI's. Each patient varies in their response and ability to tolerate a specific medication and dosage, so medications must be tailored to individual needs. Research has suggested that maximum benefit from SSRI treatment depends upon adequate dosages and duration of treatment. Treatment adherence is key to successful pharmacotherapy treatment for PTSD. Examples of the SSRI's and some typical dosage ranges are listed below:
* sertraline (Zoloft) 50 mg to 200 mg daily
* citalopram (Celexa) 20 mg to 60 mg daily
* paroxetine (Paxil) 20 to 60 mg daily
* fluoxetine (Prozac) 20 mg to 60 mg daily
Note: Only Sertraline and Paroxetine have been approved for PTSD treatment by the FDA. All other medications described in this guide are being used "off label" and may have empirical support but have not been through the FDA approval process for PTSD
Other Newer Antidepressants for PTSD. Antidepressants that work through other neurotransmitter combinations or through different mechanisms for altering serotonin neurotransmission are also helpful in PTSD. Venlafaxine acts primarily as a serotonin reuptake inhibitor at lower dosages and as a combined serotonin and norepinephrine reuptake inhibitor at higher dosages. It appears to be a first-line treatment for PTSD based upon large multi-site RCTs (6). There have been smaller RCT's with mirtazapine as well as open trials (7). Mirtazapine may be particularly helpful for treatment of insomnia in PTSD. Trazodone is also commonly used for insomnia in PTSD even though there is little empirical evidence available for its use. Nefazodone is still available in a generic form but carries a black box warning regarding liver failure, so liver function tests need to be monitored and precautions taken as recommended in the medication's prescribing information (8, 9). Examples of the newer antidepressants for PTSD and some typical dosage ranges are listed below:
* ulmirtazapine (Remeron) 7.5 mg to 45 mg daily
* venlafaxine (Effexor) 75 mg to 300 mg daily
* nefazodone (Serzone) 200 mg to 600 mg daily
All of the antidepressants described above are also effective in treating co-morbid Major Depressive Disorder (MDD) which often accompanies PTSD. While bupropion is useful in treating comorbid MDD, it has not been shown effective for PTSD in controlled trials (10). A recent trial showed superior outcomes on MDD when mirtazapine was combined initially with antidepressants vs. patients being randomized to monotherapy with fluoxetine (11). This raises important questions regarding costs, side effects, and patient preferences which merit further study.
Mood Stabilizers for PTSD. Despite some promising open label studies, recent RCT's have been negative for this group of medications in treating PTSD (12). They could be helpful in the treatment of co-morbid Bipolar Disorder and PTSD, however. For patients who have Bipolar Disorder and PTSD, these medications are useful due to the potential for antidepressants to precipitate a manic episode. Most require some regular lab work to monitor side effects. Lamotrigine does not require lab work but must be titrated slowly according to package insert directions to avoid a potentially serious rash. Examples are given below:
* Carbamazepine (Tegretol): Requires monitoring of white blood cell counts due to risk of agranulocytosis. Will self-induce its own metabolism and increase the metabolism of other medications including oral contraceptives.
* Divalproex (Depakote): Requires monitoring of liver function tests due to risk of hepatotoxicity and platelet levels due to risk of thrombocytopenia. Target dosage is 10 times the patient's weight in pounds.
* Lamotrigine (Lamictal): Requires slow titration according to the package insert due to risk of serious rash.
Atypical Antipsychotics for PTSD.While originally developed for patients with a psychotic disorder, this class of medications is being applied to patients with many other psychiatric disorders including PTSD. They act primarily on the dopaminergic and serotonergic systems and are being used in PTSD for improving hyperarousal and re-experiencing symptoms. The evidence is mixed on their use as adjunctive therapy in PTSD for patients who have residual symptoms following the use of first line agents such as SSRI's and venlafaxine (13).
There is currently one positive trial for risperidone as monotherapy. This trial studied women with PTSD related to sexual assault and domestic abuse. There are three positive trials and two negative trials of risperidone as adjunctive therapy. Many of the studies using risperidone as adjunctive therapy included veterans with combat trauma. For olanzapine, there is one negative trial as monotherapy and 1 positive trial as adjunctive therapy. There are currently no published randomized placebo controlled trials for any of the other atypical antipsychotic agents.
These medications must be used with caution and require monitoring of blood glucose levels and cholesterol levels as they may cause elevation. There is also a small risk of developing extrapyramidal side effects and tardive dyskinesia and more rare side effects such as neuroleptic malignant syndrome. These medications are also effective for comorbid psychotic and mood disorders for which they are approved. Dosages vary widely, so please refer to package insert for dosing ranges.
* Olanzapine (Zyprexa)
* Risperidone (Risperdal)
Other Medications for PTSD. There are a number of other medications that can be helpful for specific PTSD symptoms or that have been used as second line agents including the following:
* Prazosin (Minipress)
* Tricyclic Antidepressants (such as Imipramine)
* Monoamine Oxidase Inhibitors (MAOI's) (such as Phenelzine)
Prazosin has been found to be effective in RCTs in decreasing nightmares in PTSD. It blocks the noradrenergic stimulation of the alpha 1 receptor. It has not been found to be effective for PTSD symptoms other than nightmares at this time (14). The tricyclic antidepressants and MAOI's act on a number of neurotransmitters. While there are RCT's supporting their use, these medications are not used as first line agents due to their safety and side effect profiles (15, 16). The tricyclics have quinidine like effects on the heart and can cause ventricular arrhythmias especially in overdose. The MAOI's can cause potentially fatal reactions due to hypertensive crisis when taken with other medications or certain foods rich in tyramine. MAOI's can also provoke the potentially fatal serotonin syndrome when used concurrently with SSRI's.
Buspirone and beta blockers are sometimes used adjunctively in treatment of hyperarousal symptoms, though there is little empirical evidence in support of this. Buspirone acts on serotonin and might reduce anxiety in PTSD without sedation or addiction. There are some case reports supporting its use. Beta blockers block the effects of adrenalin (epinephrine) on organs such as the heart, sweat glands, and muscles. There is interest in using beta blockers to prevent PTSD, though the evidence at this time does not support this. Beta blockers reduce the peripheral manifestations of hyperarousal and may reduce aggression as well. They may be used for comorbid conditions such as performance anxiety in the context of social phobia for example.
Benzodiazepines and PTSD. Benzodiazepines act directly on the GABA system which produces a calming effect on the nervous system. This is the only potentially addictive group of medications discussed. Studies have not shown them to be useful in PTSD treatment as they do not work on the core PTSD symptoms (17, 18). There are several other concerns with the benzodiazepines including potential disinhibition, difficulty integrating the traumatic experience, preventing optimal arousal in prolonged exposure therapy, and addiction. Because of their potential for addiction and disinhibition, they must be used with great caution in PTSD. Examples are listed below:
* Lorazepam (Ativan)
* Clonazepam (Klonopin)
* Alprazolam (Xanax)
Developing new medications for PTSD:
The pathophysiological mechanism of PTSD in the nervous system is unknown, but there are several interesting areas that could lead to new drug development for the treatment or the prevention of PTSD. There are competing hypotheses about the role of glucocorticoids following trauma and their effects on the brain. It might be possible to intervene at some level in the hypothalamic-pituitary-adrenal axis or at the level of the glucocorticoid receptors in the brain to modulate the effects of stress and the development of PTSD. Neuropeptides such as Substance P and Neuropeptide Y (NPY) have been implicated in PTSD as well (19). Combat troops exposed to stress have been found to have lower levels of NPY. Perhaps altering this neuromodulator could improve the resiliency of the brain to the effects of trauma. One challenge with this research is dealing with the blood-brain barrier for introducing neuropeptides into the brain. Memantine (Namenda) is a drug of much interest in preventing neurodegeneration by protecting against glutaminergic destruction of neurons. It has been approved for use in certain neurodegenerative conditions such as Alzheimer's disease. This drug could be potentially useful in preventing hypothesized neurodegneration in the hypothalamus and memory loss in PTSD. D-cycloserine has been used in panic disorder to enhance the effects of exposure therapy (20). It is a partial agonist of the N-methyl-D-aspartate (NMDA) receptor. Current research is looking towards the possibility of one day intervening early in the course of PTSD with a combination of psychotherapy and pharmacotherapy that would prevent the development of the pathophysiology of PTSD in the brain.
Common barriers to effective medication treatment in PTSD:
There are several common barriers to effective medication treatment for PTSD which are listed below. These need to be addressed with patients in an ongoing dialogue with their prescribing clinician. Side effects need to be examined and discussed, weighing the risks and the benefits of continued medication treatment. Patient education about the side effects, necessary dosages, duration of treatment, and taking the medications consistently can improve adherence. A simple intervention of setting up a pill organizer weekly can go a long way to improve adherence.
* fear of possible medication side effects including sexual side effects
* feeling medication is a "crutch" and that taking it is a weakness
* fear of becoming addicted to medications
* taking the medication only occasionally when symptoms get severe
* not being sure how to take the medication
* keeping several pill bottles and not remembering when the last dosage was taken
* using "self medication" with alcohol or drugs with prescribed medications
A final word regarding medications and treatment for PTSD:
A more comprehensive discussion of pharmacotherapy can be found online in the VA/DoD PTSD Clinical Practice Guidelines. Based upon current knowledge, most prescribing clinicians view pharmacotherapy as an important adjunct to the evidenced based psychotherapies for PTSD. While there are few direct comparisons of pharmacotherapy and psychotherapy, the greatest benefits of treatment appear to come from evidenced based therapies such as CPT, PE, and patients need to be informed of the risks and benefits of the differing treatment options. When using a combined approach of medication and therapy, it is important to keep several practices in mind. If treatment is being provided by a therapist and a prescriber, it is important for the clinicians to discuss treatment response and to coordinate efforts. It is important for the prescribing clinician to have an ongoing dialogue with the patient about their medications and side effects. It is important for the patient to take an active role in his or her treatment rather than feeling they are a passive recipient of medications to alleviate their symptoms. There is emerging evidence that when given a choice, most patients will select psychotherapy treatment for their PTSD symptoms rather than medications.
Patients with anxiety disorders including PTSD may be very aware of their somatic reactions, and it is important to start low and go slow often on dosage adjustments to improve patient adherence. Be sure to ask female patients of childbearing age about contraception when prescribing medication. Be sure to ask all patients about substance abuse as well. Once mediations are started, it is crucial that the provider remember to discontinue medications which are not proving efficacious and to simplify the number and types of medications used whenever possible.
References:
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2. Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry. 2001 Dec;158(12):1982-8.
3. Randomized, double blind comparison of sertraline and placebo for posttraumatic stress disorder in Department of Veterans Affairs setting. Friedman MJ, Marmar CR, Baker DG, Sikes CR, Farfel GM. J Clin Psychiatry. 2007 May; 68(5):711-20.
4. Yehuda R, Bierer LM. Transgenerational transmission of cortisol and PTSD risk. Prog Brain Res. 2008; 167:121-35.
5. Lanius RA, Vermetten E, Loewenstein RJ, Brand B, Schmahl C, Bremner JD, Spiegel D. Emotion modulation in PTSD: Clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry. 2010 Jun; 167(6):640-7.
6. Davidson J, Baldwin D, Stein DJ, Kuper E, Benattia I, Ahmed S, Pedersen R, Musgnung J. Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry. 2006 Oct;63(10):1158-65.
7. Chung MY, Min KH, Jun YJ, Kim SS, Kim WC, Jun EM. Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial. Hum Psychopharmacol. 2004 Oct;19(7):489-94.
8. Davis LL, Jewell ME, Ambrose S, Farley J, English B, Bartolucci A, Petty F. A placebo-controlled study of nefazodone for the treatment of chronic posttraumatic stress disorder: a preliminary study. J Clin Psychopharmacol. 2004 Jun;24(3):291-7.
9. McRae AL, Brady KT, Mellman TA, Sonne SC, Killeen TK, Timmerman MA, Bayles-Dazet W. Comparison of nefazodone and sertraline for the treatment of posttraumatic stress disorder. Depress Anxiety. 2004;19(3):190-6.
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13. Pae CU, Lim HK, Peindl K, Ajwani N, Serretti A, Patkar AA, Lee C. The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Int Clin Psychopharmacol. 2008 Jan;23(1):1-8.
14. Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D, Shofer J, O'Connell J, Taylor F, Gross C, Rohde K, McFall ME. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007 Apr 15;61(8):928-34.
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17. Braun P, Greenberg D, Dasberg H, Lerer B. Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry. 1990 Jun;51(6):236-8.
18. Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996 Sep;57(9):390-4.
19. Morales-Medina JC, Dumont Y, Quirion R. A possible role of neuropeptide Y in depression and stress. Brain Res. 2010 Feb 16; 1314:194-205.
20. Otto MW, Tolin DF, Simon NM, Pearlson GD, Basden S, Meunier SA, Hofmann SG, Eisenmenger K, Krystal JH, Pollack MH. Efficacy of d-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol Psychiatry. 2010 Feb 15;67(4):365-70.
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