CNS Spectr. 2004;9(10):740-752

Dr. Hamner is professor in the Department of Psychiatry and Behavioral Sciences at the Medical University of South Carolina (MUSC) and director of the PTSD Clinical Treatment Team and Psychiatry Research Section at the Ralph H. Johnson Veterans Affairs (VA) Medical Center, both in Charleston. Dr. Robert is assistant professor in the Department of Psychiatry and Behavioral Sciences at MUSC and at the Ralph H. Johnson VA Medical Center. Dr. Frueh is associate professor in the Department of Psychiatry and Behavioral Sciences at MUSC and staff psychologist at the Ralph H. Johnson VA Medical Center.

Disclosure: Dr. Hamner has received grants from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, Janssen, Johnson & Johnson, Otsuka, and Sanofi Synthélabo, is on the speakers bureau of Abbott, AstraZeneca, Bristol-Myers Squibb, Forest, Janssen, Otsuka, Shire, and Wyeth, is a consultant for AstraZeneca, and Johnson & Johnson, and he holds stock in Pfizer. This paper was submitted on March 15, 2004, and accepted on August 9, 2004.

Please direct all correspondence to: Mark B. Hamner, MD, Mental Health Service 116, Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401; Tel: 843-789-7799, Fax: 843-577-4577; E-mail: hamnermb@musc.edu.

Abstract

Introduction 

Posttraumatic stress disorder (PTSD) is currently defined as an anxiety disorder that may develop after experiencing severe psychological trauma such as combat, rape, or other violent crimes, natural disasters, or accidents.¹ The three symptom clusters that characterize the condition include reexperiencing, avoidance and numbing, and hyperarousal symptoms. These symptoms must be present for at least 1 month and cause significant distress or functional impairment to meet diagnostic criteria.¹ Importantly, the reexperiencing symptoms such as intrusive memories or flashbacks, or nightmares, are considered the “core” features of PTSD and differentiate the disorder from other anxiety disorders. On the other hand, there is considerable overlap between PTSD symptoms and other anxiety and mood disorders.¹ For example, intrusive memories of the trauma are similar to obsessions in obsessive compulsive disorder, flashbacks have many symptoms in common with panic attacks, avoidance symptoms overlap with phobic disorders (eg, social anxiety disorder) and hyperarousal symptoms are all symptoms that occur in generalized anxiety disorder. Many symptoms overlap with depressive symptoms (eg, insomnia, irritability, difficulty concentrating, anhedonia, and sense of foreshortened future). In addition to the heterogeneity of symptoms and phenomenological overlap with other disorders, there is considerable comorbidity with other psychiatric disorders, including major depression and other mood disorders, alcohol and substance abuse, dissociative disorders, personality disorders, and psychotic disorders or psychotic features.^2,3

The symptom complexity and comorbidities are important to appreciate for clinicians treating patients suffering from chronic PTSD. As may be readily apparent, there may not be a single treatment approach that will alleviate all of the symptoms in PTSD. As such, most clinicians now accept that combinations of psychotherapeutic approaches and possibly combinations of medications may be needed to benefit patients with PTSD. 

Antidepressant medications have been the mainstay of treatment for PTSD. A number of controlled trials^4-17 now support the efficacy of these agents in PTSD with studies including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and other new generation antidepressants including mirtazapine and venlafaxine. Earlier antidepressant trials (as well as more contemporary studies) tended to have mixed results in terms of which PTSD symptoms responded to treatment. Overall negative studies tended to have inadequate sample sizes or were too brief in duration. Most of the earlier antidepressant studies were conducted in combat veterans with PTSD. Two landmark positive trials^4,5 were with imipramine and phenelzine, each compared with placebo and amitriptyline compared with placebo. Treatment effect sizes tended to be modest in these studies. Additional knowledge gleaned from earlier trials as well as the larger regulatory studies suggested that treatment duration (≥8 weeks) had a significant influence on outcome in antidepressant treatment. 

Two SSRIs are now Food and Drug Administration (FDA)-indicated for PTSD based on randomized, placebo-controlled, multicenter trials. These include sertraline^6,7 and paroxetine.^8,9 There are published, placebo-controlled trials^10-17 with a number of other antidepressants including brofaromine, fluoxetine, citalopram, nefazodone, venlafaxine, and mirtazapine.

Antidepressant Trials: Defining Response and the Issue of Residual Symptoms 

Although considered the mainstay treatments for PTSD, many patients do not have an adequate therapeutic response to antidepressants alone. There has been some suggestion that combat veterans with PTSD may not be as likely to respond to antidepressants as civilian trauma victims.^18-21 A number of reasons have been proposed to explain this, including longer duration of PTSD symptoms, older age, male gender, severity of PTSD illness, and comorbidity with other psychiatric illnesses, including mood disorders, substance abuse, and psychotic disorders. There has been a paucity of published literature specifically investigating treatment-refractory PTSD strategies. Most experts²² agree that optimizing psychotherapy is important.From a medication standpoint, many experts would consider adding a second antidepressant, a mood-stabilizer, an anti-adrenergic agent, or an atypical antipsychotic agent.²³ There is no commonly accepted definition of treatment-resistant PTSD. 

One current definition of clinical response to antidepressant medication is having ≥30% reduction in Clinician Administered PTSD Scale (CAPS)²⁴ scores. This contrasts with a common criterion of response in depression (ie, ≥50% reduction in Hamilton Depression Scale²⁵ scores) but is similar to criteria for response to antipsychotics in schizophrenia (eg, 30% decline in Positive and Negative Symptom Scale²⁶ ratings). 

It is also important to note that even in patients who have improvement in PTSD symptoms, most will still meet criteria for PTSD at the end of an adequate treatment trial (Table 1). Therefore, with existing antidepressants, there may be a significant number of patients who do not meet criteria for response to the agent and, even among those patients meeting criteria for response, there may still be a significant illness burden with associated functional impairment.

Hamner and Frueh³¹ reported a single case of a patient who failed several antidepressant treatment trials but improved with venlafaxine.This is of interest in light of some literature supporting a role for venlafaxine in SSRI-resistant depression. In a recent multicenter, double-blind, placebo-controlled PTSD study,¹⁶ venlafaxine was significantly better than placebo on more outcomes measures than sertraline, including the primary outcome measure (change in CAPS scores) and remission rates. Onset of effect was apparent as early as Week 2 with venlafaxine versus Week 6 with sertraline. Mirtazapine has also been compared to sertraline in a 6-week trial in Korean veterans with PTSD.³⁰ Although average reductions in CAPS scores did not differ significantly between the two groups, more patients responded to mirtazapine based on a response criteria of ≥30% decrease in CAPS scores, ≥50% decrease in HAM-D scores, and a Clinical Global Impression score of at least “much improved.” These results are promising, however the shorter trial duration of 6 weeks versus 12 weeks, and lower average sertraline dosage of 101 mg/day compared with 133–146 mg/day in regulatory trials^6,7 may have undermined sertraline’s potential efficacy in this trial. 

Several published open-label trials suggest that nefazodone may be effective at reducing PTSD symptoms, including sleep disturbances, even in some patients who have failed other antidepressants. Zisook and colleagues³² enrolled veterans with chronic PTSD who had failed at least three previous trials of antidepressants in a 12-week open-label, monotherapy trial of nefazodone. The CAPS frequency and intensity scores decreased by 31% and 32%, respectively, and improvement was noted on several other outcome measures. Although promising, these findings need replication in controlled studies. 

Exposure Therapy and Other Psychosocial Therapies 

Although a range of psychotherapeutic interventions for PTSD have been suggested, cognitive-behavioral treatments, emphasizing exposure, or cognitive restructuring show the most evidence of efficacy. In fact, evidence-based treatment guidelines for PTSD focus heavily on cognitive-behavioral interventions.^33,34 Studies indicate that exposure therapy helps^38-40 reduce the hallmark features of PTSD (eg, symptoms of intrusion and physiological reactivity) and much of the attendant distress that accompanies it. According to the Consensus Statement on Posttraumatic Stress Disorder by the International Consensus Group on Depression and Anxiety, the most appropriate psychotherapy for the disorder is exposure.^22,35,36

Overall, studies³⁷ that have examined the efficacy of exposure treatment for PTSD in veteran samples have yielded mixed gains across symptoms measures. Studies in civilian samples,^23,33,34 while yielding symptom improvement on the majority of outcome measures, reveal that exposure alone is not sufficient for a significant number of patients. Furthermore, although exposure may reduce maladaptive arousal and fear, it does not address basic skill deficits, help reestablish impaired relationships, or improve anger management. Therefore, exposure therapy does not appear to help the social impairment that is characteristic of chronic PTSD. Keane³⁸ and Frueh and colleagues³⁹ have suggested that comprehensive programs targeting specific areas of dysfunction via different behavioral strategies is necessary to address the complex symptoms associated with this condition. Towards this end, exposure therapy has been combined with stress inoculation (eg, use of coping skills under therapist-controlled stress conditions),⁴⁰ cognitive-behavioral group therapy,⁴¹ behavioral family therapy,⁴² anxiety management training (eg, coping skills),⁴³ substance abuse treatment,⁴⁴ inpatient milieu therapy,⁴⁵ and specifically targeted social skills training.^37,39 These preliminary data indicate that stress inoculation and behavioral family therapy did not add to the benefits of exposure therapy, while uncontrolled data suggest that there may be some promise for general anxiety management, cognitive-behavioral group therapy, targeted substance abuse components, and social skills training. On the other hand, a recent literature review suggests that treatment effects may be diminished by diluting exposure therapy when supplementing it with other treatment components.⁴⁶

A common clinical impression is that psychotherapy, in particular cognitive-behavioral therapy (CBT), combined with antidepressant medication is likely to facilitate clinical responses in PTSD, analogous to combining psychotherapy with medication in the treatment of major depression. Emerging data now support this notion. A pilot study by Otto and colleagues⁴⁷ suggests that combination treatment with CBT is more effective than sertraline alone in medication-resistant PTSD. Results from another study⁴⁸ suggest that paroxetine or CBT are both effective for acute treatment (3 months) but that the effects of CBT may outlast those of medication after treatment discontinuation. Combination of prolonged exposure (PE) and medication has also been explored. In the largest study presented to date, Cahill and colleagues⁴⁹ noted some additional benefits of combining PE to sertraline versus continuing with sertraline alone in patients who had previously responded to a 10-week course of the medicine. At a 6-month follow-up, patients who had received the combination tended to maintain their gains better than those who had received sertraline alone, although this difference was not statistically significant. 

Secondary Gain Issues and Impact on Treatment Outcome 

It is well accepted that persons with mental illnesses often experience severe occupational impairment and related financial hardships.^50,51 Unfortunately, many efforts to address this concern, such as disability payments, lead to secondary gain incentives that may influence the evaluation and treatment of PTSD. There is some evidence that disability-seeking influences treatment outcome. In a large sample of inpatient and outpatient veterans treated for PTSD at Veterans Affairs Medical Centers, it was found that compensation-seeking status had a significant treatment effect for inpatients (ie, less likely to improve), but not for outpatients.⁵² This is an understudied issue, and further research is needed. Clinicians and investigators should, as a matter of routine practice be aware of the disability status of those receiving treatment, and consider how financial secondary gain incentives may impact treatment outcome.⁵³ 

Medication Augmentation or Combination 

Of initial concern for any patient is whether they have had an adequate treatment trial of the medication (ie, adequate dose for an adequate length of time). Although most antidepressant studies suggested that there is a flat dose-response curve, at least for the antidepressant doses studied to date, most experts recommend increasing the antidepressant dose to maximum as tolerated. The adequate trial length is likely to be ≥8 weeks, with some data from sertraline continuation studies that there may be continued improvement for subsequent weeks.⁵⁵ Longer treatment following an initial acute response can sustain symptomatic and quality of life improvements, and decrease the risk of relapse.^54-57 As always, patients should be asked about medication adherence. Many will not take a medication due to perceived lack of efficacy or side effects such as sexual dysfunction^58,59 and may be embarrassed to tell the physician unless asked or given permission to do so. With the SSRIs, another reason for nonadherence is sleep disruption, with some patients reporting more vivid dreams or nightmares and associated insomnia.⁵⁹ Ideally, medication monotherapy will be effective for the patient. However, “rational polypharmacy” may be indicated to enhance tolerability of medications or to increase efficacy. As an example, a benzodiazepine may be given concurrent with an SSRI to help minimized early activation effects of the SSRI. The benzodiazepine could later be tapered and discontinued. The addition of low-dose trazodone, or other sedative agents may facilitate sleep and also help reduce SSRI-associated sleep disturbances. Pharmacodynamic considerations should factor into decisions to add medications. For example, the addition of an anti-adrenergic agent, such as prazosin,⁶⁰ would compliment an SSRI due to data suggesting exaggerated norepinephrine release in PTSD. With this in mind, the following strategies may be considered for augmenting antidepressant medications.⁶¹ 

Second Antidepressant 

Trazodone added to SSRIs is one common approach, in particular for patients who have continued sleep disturbances but have achieved some benefit from the SSRI. Common doses of trazodone are in the range of 25–300 mg QHS.⁶² Side effects include sedation, especially excessive morning somnolence, postural dizziness, and the rare risk of priapism. Bupropion has also been used as a monotherapy or combination strategy. From a pharmacodynamic standpoint, this would add dopamine and noradrenergic action to the serotonergic effects, if the agent is added to an SSRI. ⁶³ The addition of bupropion may also help reduce SSRI-induced sexual dysfunction.⁶⁴ Nefazodone, like trazodone, may benefit sleep but has the added recent warning by the FDA of hepatitis risk. Mirtazapine also may benefit sleep.⁶⁵ Low-dose tricyclic antidepressants may also be useful (eg, 25–100 mg QHS of amitriptyline or imipramine) to facilitate sleep. Caution is warranted with the TCAs due to their low therapeutic index, cardiac conduction effects, and potent anticholinergic and anti-adrenergic effects. 

Mood Stabilizers 

There has been surprisingly little published literature with lithium or with anticonvulsant mood stabilizers in PTSD despite early promising reports with these agents. Lithium has been reported to be efficacious as an adjunct to antidepressants in refractory major depression.⁶⁶ Case reports^67,68 have suggested potential efficacy of lithium, especially for irritability, in PTSD but to our knowledge there have been no prospective studies. Side effects of lithium are well known and should be taken into consideration, in particular in patients with suicidality or significant medical illnesses such a renal impairment that may affect fluid and electrolyte balance. 

Anticonvulsant mood stabilizers are of interest in PTSD because of their antikindling activity.⁶⁹ Kindling involves subthreshold electrical or chemical brain stimulation eventually leading to full-blown seizures. After chronic stimulation, the seizures can occur spontaneously.^69,70 This model may be applicable to several neuropsychiatric disorders, including PTSD. Repeated traumatization or a trauma followed by intrusive re-experiences might kindle limbic nuclei, leading to some of the emotional, cognitive, and behavioral changes observed in PTSD.⁶⁹ Case reports, retrospective studies, and open trials have supported potential efficacy for divalproex,^71-74 carbamazepine,^75,76 topiramate,^77,78 tiagabine,⁷⁹ and gabapentin⁸⁰ either alone or in combination with other agents. Two double-blind, placebo-controlled trials of divalproex^81,82 failed to confirm positive findings of earlier open-label studies, however. This may have been due to a lack of efficacy of divalproex, inadequate sample size to detect differences between divalproex and placebo, low valproate plasma levels, or other factors such as non-adherence. 

There is only one published controlled monotherapy trial of an anticonvulsant in PTSD. Hertzberg and colleagues⁸³ studied lamotrigine versus placebo in 14 subjects with PTSD who underwent a 12-week double-blind evaluation. Of 10 patients who received lamotrigine, 50% responded as compared with 25% response for the placebo group. These findings are encouraging but need replication in a larger study. There are a number of controlled anticonvulsant mood stabilizer trials now in progress and hopefully in the next several years the role of these agents will be better defined in PTSD.

Anti-anxiety Agents and Hypnotics 

Anxiolytics may include a wide spectrum of agents, for this section benzodiazepines, buspirone, and new-generation hypnotics will be addressed. Despite their widespread use in PTSD, there has been little systematic study of the efficacy and safety of benzodiazepines or other anxiolytics in PTSD. 

Most studies have been negative or inconclusive regarding their efficacy in PTSD. A controlled study⁸⁴ with alprazolam failed to differentiate the effects of alprazolam from placebo for core PTSD symptoms although anxiety improved. An interesting neuroimaging report by Bremner and colleagues⁸⁵ suggested reduced frontal cortical benzodiazepine binding in combat veterans with PTSD. This may help explain the common clinical observation that many of the chronic PTSD veteran patients require relatively high doses of benzodiazepines, if administered. Regarding early intervention with benzodiazepines, Mellman and colleagues⁸⁶ reported a case series of trauma survivors with acute PTSD symptoms, including sleep disturbances, who benefited from brief treatment with the benzodiazepine hypnotic temazepam. Improvement persisted after drug discontinuation. Another group of investigators,⁸⁷ however, did not observe long-term benefits of early intervention with benzodiazepines. Drawbacks to the use of benzodiazepines include concerns about substance abuse, physiological dependence, and cognitive and motor impairment. There have also been reports of behavioral disinhibition occurring with benzodiazepines. In contrast to concerns about use of benzodiazepines in the chronic PTSD population, a recent report by Kosten and colleagues⁸⁸ suggested that benzodiazepine treatment in veterans with PTSD and comorbid substance abuse was not associated with increased adverse effects or altered treatment outcome, although the substance abuse patients were less likely to be prescribed benzodiazepines.

Buspirone is an anxiolytic agent with serotonin 1A receptor partial agonist effects. Its advantages include a high therapeutic index, relatively benign side-effect profile (eg, minimal sexual dysfunction, lack of addictive potential) and now lower cost as it is generic. Buspirone has been used to augment antidepressants in refractory major depression, largely based on open-label studies^89-91 since more recent controlled trials have shown limited efficacy at best. Case reports and case series^92-95 have also suggested that it may be useful in PTSD. In the largest published report⁹⁵ to date, we conducted a retrospective review of the effectiveness of buspirone when used as an adjunctive agent. In this study, a positive response to buspirone augmentation of antidepressants occurred in 11 of 14 patients (73%) based on retrospective clinical global impressions ratings.The average dose of buspirone in responders was 40 mg (range 30–60 mg/day) and all patients were taking a serotonergic antidepressant prior to initiation of the buspirone.

Sleep disturbances are often the most refractory symptoms in PTSD and, in fact, may at times be exacerbated by some of the antidepressants. A number of classes of agents have been utilized in combination with antidepressants to facilitate improved sleep. A case series with zolpidem⁹⁶ appeared promising in combat veterans with PTSD. As noted above, low-dose trazodone, tricyclic antidepressants, and gabapentin have also been utilized to enhance sleep. There have been a few reports of cyproheptadine, an antihistamine and serotonin 2A receptor antagonist, facilitating sleep.^97-99 In the next section, we will address the potential utility of anti-adrenergic agents and also certain atypical antipsychotics in terms of potential sleep benefits.

Anti-adrenergics 

The use of anti-adrenergics is based on preclinical learned helplessness models and clinical studies in patients with PTSD consistent with exaggerated release of norepinephrine. For example, exaggerated release of norepinephrine and its primary brain metabolite 3-methoxy-4 hydroxyphenylglycol has been described in response to psychological, pharmacological, and physical stressors. Many of the physiological arousal symptoms of PTSD are mediated by central and peripheral norepinephrine alterations as demonstrated in laboratory settings. 

Early open trials of the α₂ adrenergic agonist clonidine^100,101 (which blocks central norepinephrine outflow from the locus ceruleus) and with the β-adrenergic receptor antagonist propranolol were promising in reducing PTSD symptoms in various populations, including a study in children. Recently, a controlled trial of the α₁ adrenergic receptor antagonist prazosin showed promise in reducing insomnia and nightmares associated with PTSD.⁶⁰ Doses of prazosin utilized in this study averaged 10 mg, higher than the usual dose range for urologic purposes. Caution is warranted with the anti-adrenergics to observe for postural hypotension or tachycardia. 

A recent controlled study by Pitman and colleagues¹⁰² suggested that propranolol could reduce severity of later PTSD symptoms in trauma victims. This study was based on a report by Cahill and colleagues¹⁰³ that propranolol could reduce cognitive responses to emotionally laden scripts. Findings similar to those of Pitman and colleagues¹⁰² were reported by Vaiva and colleagues¹⁰⁴ in a non-randomized, open-label propranolol treatment with blind assessments. If replicated by larger, adequately powered, randomized studies, these findings could support use of propranolol as an early intervention in PTSD. 

Atypical Antipsychotics 

There is an emerging interest in the use of atypical (or new generation) antipsychotics in PTSD. Although some earlier case reports with typical antipsychotics were promising in terms of efficacy, there have been concerns about the risk of side effects, in particular extrapyramidal side effects such as tardive dyskinesia. Thus, the use of typical antipsychotics in a potentially nonpsychotic population was more controversial. Two possible indications for the use of atypical agents would include treatment-resistant PTSD or for PTSD with comorbid psychotic features of psychotic disorders. Another consideration would be in PTSD with comorbid bipolar disorder since several of the atypicals are now FDA-approved for the treatment of bipolar mania^105-107 and now olanzapine is FDA-approved for maintenance treatment¹⁰⁷ and olanzapine-fluoxetine combination is approved for bipolar depression.¹⁰⁸ The rationale for studying atypicals in PTSD includes the effects of these agents on neurotransmitter systems implicated in PTSD (eg, norepinephrine, serotonin, and dopamine). Their potential efficacy in treatment-resistant major depression, which is frequently comorbid with PTSD, their emerging use in other anxiety disorders, including obsessive-compulsive disorder, which share symptoms and phenomenology with PTSD, the relatively frequent comorbidity with psychosis in PTSD, and the broader psychotropic effects of this class of agents (ie, they do not affect just classical positive symptoms of psychosis such as hallucinations but also may reduce negative and general psychopathology symptoms). Studies of their use in schizophrenia first demonstrated these broader psychotropic effects (eg, anxiety symptoms in the context of schizophrenia) showed improvement. The most common primary outcome measure used in recent schizophrenia regulatory trial,s the Positive and Negative Symptoms Scale²⁶ includes a wide range of psychiatric symptoms and demonstrated responses in these symptoms to atypical agents. When Hamner and colleagues¹⁰⁹ compared a group of PTSD patients with comorbid symptoms with a group of schizophrenia patients using Positive and Negative Symptoms Scale ratings, the groups were remarkably similar in global symptom burden, the primary difference being in complexity or severity of the psychotic symptoms in the schizophrenia patients.

This highlights the global symptoms burden that chronic PTSD patients have and also provides further rationale for studying the atypicals in this population. Several studies have also suggested a relative high frequency of psychotic symptoms at least in the chronic combat-associated PTSD population.^110,111 The symptoms are often referable to the traumatic experience and may include phenomena such as auditory hallucinations of incoming rocket fire or soldiers screaming or visual hallucination of enemy soldiers. They clearly may overlap with characteristic reexperiencing symptoms. Studies have suggested that psychotic symptoms tend to be correlated with severity of PTSD symptoms and with comorbid depression.^112,113

Several case reports, open-label trials, and some controlled studies of atypical agents, mostly used adjunctively, have reported improvement in overall PTSD psychopathology, psychosis, depression, and in specific PTSD symptoms such as irritability, flashbacks, nightmares, and other sleep disturbances. Most of these reports were in combat veterans who had failed or had minimal response to several other medication treatments. 

Of particular relevance to the current paper, Stein and colleagues¹¹⁸ studied a group of combat veterans who were refractory to selective serotonin reuptake inhibitor antidepressants. The added olanzapine and noted significant improvement in global PTSD symptoms and that sleep parameters in particular improved. To our knowledge, this is the only study in the PTSD literature that has prospectively treated a cohort of patients and then added an adjunctive therapy for initial nonresponders. 

Conclusion

Although CBT (exposure therapy) and antidepressants (mainly SSRIs) are considered state of the art treatments for PTSD, many patients still have significant symptoms at the conclusion of adequate treatment trials with these approaches. A number of factors may contribute to refractoriness in PTSD including severity of illness, suffering multiple traumas, chronicity of illness, gender (male), type of trauma (combat), secondary gain issues, severity and number of comorbid psychiatric illnesses such as psychosis, and other factors. There is a great need for studies to investigate the efficacy of combination or adjunctive strategies in patients who are refractory or have at best a partial response to standard treatments. Although still in its relative infancy, the initial data on combination strategies is promising in suggesting that adding certain psychotropics may further clinical response in refractory PTSD agents.

At the present time, there is insufficient data to make a clear evidence-based recommendation as to what to do next for the patient who has not had an adequate response to the initial treatment. Certainly, psychotherapy should be optimized if this has not been done and compliance (with antidepressant medication) assessed. As reviewed above, there is emerging data to support the use of a second antidepressant, a mood stabilizer, an anti-adrenergic agent/hypnotic, or an atypical antipsychotic agent in PTSD. The individual approach may be based on primary target symptoms (eg, use of a hypnotic or more sedating atypical antipsychotic if there are prominent sleep disturbances). A mood stabilizer may help for prominent refractory mood lability or aggression. Psychotic features or diagnoses would call for the use of an atypical antipsychotic. Future clinical studies should help address the risk-benefit ratios, including pharmacoeconomic considerations, of utilizing combinations of treatments. Hopefully, better understanding of the neurobiological basis of PTSD will help guide more sophisticated treatment interventions, including early intervention and prevention. A more comprehensive understanding of risk factors for PTSD may also help identify both individuals at risk for PTSD subsequent to trauma as well as individuals who may be more refractory to treatment. 

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