Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE ( © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 19 January 2019

Pharmacotherapy for Posttraumatic Stress Disorder and Other Trauma-Related Disorders

Abstract and Keywords

Posttraumatic stress disorder (PTSD) can cause serious chronic psychological impairments in a significant number of persons who have been exposed to an extreme traumatic event. Finding effective, well-tolerated pharmacological treatments for this disorder is an ongoing research effort. This chapter reviews recent thinking that PTSD results from dysfunctions in the neural systems mediating fear learning and memory. These systems are modulated by dopamine, GABA, norepinephrine, and serotonin. Drugs that have been investigated to alleviate PTSD symptoms affect these neuromodulators and include all classes of antidepressants, mood stabilizers, and antipsychotics. To date, the SSRI antidepressants, particularly paroxetine, have shown the best evidence for alleviating most PTSD symptoms in most people. Drugs that promote extinction of fear learning are currently being investigated.

Keywords: acute stress, anticonvulsants, antidepressants, antipsychotics, mood stabilizers, neurobiology, pharmacotherapy, posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a serious and complex mental disorder, which expresses itself through symptom clusters that include reexperiencing aspects of the initial trauma through intrusive trauma-related thought content, flashbacks, and nightmares; emotional numbing along with social avoidance and withdrawal; and hypervigilance with concentration impairments and sleep disturbance. Increased irritability, anger, and aggressiveness, as well as major depression and substance abuse, are also commonly seen. This disorder became officially recognized as a psychopathological entity with the recognition of the long-term difficulties experienced by war veterans, primarily related to the Vietnam conflict. The prolonged maladjustment problems often seen in soldiers returning from that campaign together with a new appreciation for the general role of trauma as a threat to psychological well-being brought sufficient attention to the syndrome that it was included in the DSM-III in 1980 (reviewed in Lasiuk & Hegadoren, 2006; McNally, 2003).

Many high-profile recent events have brought heightened attention to and concern about this issue. Tsunamis, hurricanes, earthquakes, and other natural disasters along with political events such as the war in Iraq and terrorist bombings create the seed conditions for a dramatic increase in those affected by this disorder in both the military and civilian communities. A recent study suggests that about 17% of soldiers returning from Iraq will experience serious psychological disorders (given that historic levels of violence in that region remain unchanged), with PTSD being the primary outcome (Hoge et al., 2004). Also, personally devastating events such as shootings, car accidents, rapes, and so on continue to negatively affect people's psychological well-being on an everyday basis. The personal and social cost of this disorder, the high number of (p. 406) potential new cases of PTSD, plus its widespread distribution throughout the population highlights the need for widely available, easily used, and effective treatments for acute stress and PTSD.

Posttraumatic stress disorder can be conceptualized, in essence, as a dysfunction of fear learning and memory (Bryant et al., 2005; Elzinga & Bremner, 2002; van Praag, 2004; Williams et al., 2006). It is characterized by anxiety-related behaviors and experiences that first arose as justifiable fear in response to a real threat to self or others; however, these fear responses continue for many years or decades after the initial danger has passed, and under conditions where further harm is highly unlikely. Thus, the fear learning fails to extinguish, plus the context in which the original learning occurred is lost or overgeneralized (Rothbaum & Davis, 2003). In addition, victims may show some degree of amnesia for the time period around the initial trauma, and may show chronic short-term memory impairments.

Understanding these memory dysfunctions may be important for interventions in PTSD. The sequence of events that lead to the development of PTSD are experience of an initial trauma, an intermediate period lasting from a few months to several years, where a variable number of symptoms are experienced, followed by long-term expression of PTSD symptoms. Traditionally, pharmacotherapy approaches have focused on treating the various expressions of anxiety that are the end point of the development of chronic PTSD. This often results in a lifelong regimen of medication. However, a deeper understanding of the neurobiological sequelae that place one at risk for PTSD soon after trauma has occurred has opened up possibilities for intervention much sooner in the PTSD development process. Intervention may be possible during the acute stress response, with the goal of forestalling the future development of dysfunctional fear memories. This approach is receiving increased recent attention, and some drug treatments have shown promise (Morgan, Krystal, & Southwick, 2003). Other research in memory may shed light on the processes involved in the incubation period, prior to the development of chronic symptoms. Recent investigations into memory have demonstrated that emotional memories are subject to a consolidation/reconsolidation process (McGaugh, 2004); during reconsolidation phases, memories are labile and subject to alteration, including either strengthening or extinction. This phase, wherein long-term memories are “under construction,” may be the process that is occurring during the period after trauma exposure but before the eruption of full-blown PTSD. Interventions designed to facilitate extinction during this reconsolidation phase could potentially head off the eventual development of chronic PTSD symptoms (Rothbaum & Davis, 2003). Some very encouraging progress has been made in developing treatment approaches based on this understanding (M. Davis, K. M. Myers, J. P. Chhatwal, & K. J. Ressler, 2006).

With these observations in mind, it makes great sense that investigations into the neurobiology of PTSD have focused on the neural systems for fear learning, memory, and stress responses. Since PTSD is the product of the psychological and physiological responses to a traumatic event, exploring how a pharmacotherapy for PTSD might work requires an understanding of the psychological and physiological components of the fear-learning and stress response systems. Our understanding of these interrelated systems has yielded our current knowledge of how known treatments for PTSD might be working and also suggests new avenues for the development of future interventions.

Neurobiology of Ptsd: An Overview

How do we come to appreciate that certain stimuli represent a source of threat to us, and should therefore be feared? Primates have very few, if any, instinctive fears; our repertoire of responses to aversive stimuli must be acquired from observation of others' experiences or from our own experiences. This kind of learning usually takes the form of classical conditioning, where a given set of environmental stimuli are linked up or associated with an aversive internal state (i.e., pain perception). Neural circuits that receive both types of stimuli then strengthen in activation to the previously neutral environmental stimuli. This process is the neural underpinning of associative learning, which results in a rat freezing or startling to a tone (CS+) or a person having exaggerated fear responses to stimuli that co-occurred with his or her original trauma. The system that does this learning function in the brain is for the most part subcortical and highly conserved across mammalian species. A well-developed line of research has solidly demonstrated that it is the basolateral nucleus of the amygdala (BLA) that combines sensory stimuli with internal signals produced by an aversive event. The BLA then projects to the central nucleus of the amygdala (CeA), which organizes a range of somatic and psychological responses to the threat including, presumably, the experience of the emotion of fear itself (thoroughly reviewed in M. Davis, 2000; Fanselow & Poulos, 2005; LeDoux, 1996; (p. 407) Phelps & LeDoux, 2005). Although direct evidence would be hard to obtain, a wealth of research findings predict that at the time of the experience of the initial trauma, the future victim of PTSD would have a highly activated amygdala.

The amygdala is highly interconnected with the hippocampus; the hippocampus has the important functions of encoding information about the context in which the fear learning occurred, mediating the transfer of memories into longer-term storage, and providing a source of inhibition on stress hormone release. The amygdala and hippocampus indirectly project to the paraventricular nucleus of the hypothalamus, which then initiates the hormonal aspect of the stress response (Herman et al., 2003). All of these structures have reciprocal connections with the major neuromodulatory cell body areas, including those for dopamine (DA), acetylcholine (ACh), serotonin (5-HT), and norepinephrine (NE). The drugs that are commonly used to treat PTSD exert their effects by altering the function of one or more of these neuromodulators, which then alters the limbic mediation of the experience and expression of fear and anxiety responses.

Approaches to Pharmacotherapy: Acute Stress

PTSD gradually evolves out of the responses to a specific, known event that is highly distressing. This state of affairs suggests the possibility that if the right kind of intervention is presented at the right time, perhaps the future development of PTSD could be prevented. Several recent reviews have discussed the issues to be considered for this kind of intervention to be successful (J. R. Davidson, 2006; Elsesser, Sartory, & Tackenberg, 2005; Morgan et al., 2003; Shalev, 2002). The sum of the evidence indicates that most people exhibit signs of distress in the aftermath of trauma, including hyperarousal, anxiety, reexperiencing, dissociation, numbing, agitation, and so on. For most of these victims, psychological, social, and physiological coping mechanisms will lead to a successful recovery from the trauma (Rothbaum & Davis, 2003; Shalev, 2002). A minority of trauma survivors go on to develop psychopathologies, including depression and anxiety as well as PTSD (Shalev, Freedman, et al., 1998; Yehuda, McFarlane, & Shalev, 1998). Therefore, an important concept to emerge from this line of investigation is the notion that some of the initial responses to trauma are constructive and should not be interfered with (Rothbaum & Davis, 2003). For example, it might be expected that benzodiazepine administration soon after the trauma would help to reduce hyperreactivity and promote coping responses; however, the few studies that have been done on this topic are quite variable. Beneficial effects (Mellman, Byers, & Augenstein, 1998), no effects (Braun, Greenberg, Dasberg, & Lerer, 1990), and deleterious effects (Gelpin, Bonne, Peri, Brandes, & Shalev, 1996) have all been reported. It appears that benzodiazepine-induced sedation is not conducive to mounting a coping response to the traumatic stressor (McCleery & Harvey, 2004). A more promising approach has been to use drugs that interfere with NE transmission, as it is NE that initiates the sympathetic system-mediated arousal response to immediate threat, and may also participate in the encoding of memories for such events (Hurlemann et al., 2005; Murchison et al., 2004). The β2 blocker propranolol (Famularo, Kinscherff, & Fenton, 1988; Pitman et al., 2002; Vaiva et al., 2003), when administered soon after the occurrence of trauma, was associated with a reduction in indicators of anxiety and PTSD measured 2–3 months after the trauma event. The α1 antagonist prazosin and the α2 receptor antagonist clonidine have been found to alleviate nightmares and emotional reactivity in PTSD subjects (Kinzie & Leung, 1989; Raskind et al., 2002; Taylor et al., 2006); these medications may also be efficacious for acute stress interventions.

One of the hypotheses that has been proposed to account for neurobiological processes that may be occurring during the period between trauma exposure but before the expression of full PTSD symptoms has been the mechanism of amygdalar kindling (Kalynchuk, Pinel, & Meaney, 2006; Kellett & Kokkinidis, 2004). Following this model, the use of anticonvulsants during the period soon after trauma exposure may also be efficacious (Pitman & Delahanty, 2005). Continued investigations of ways to constructively ameliorate the initial effects of trauma, and possibly circumvent the descent into PTSD (and its persistence), are clearly needed.

Approaches to Pharmacotherapy for PTSD

Some of the earliest appraisals of effective pharmacotherapy for PTSD focused on methods to reduce the hyperarousal seen in PTSD, with the expectation that other symptoms would be ameliorated as well. Drugs in use at the time to treat panic disorder and depression were explored for efficacy in PTSD, including the MAOI and tricyclic antidepressants, the benzodiazepines, and the NE antagonists, clonidine and propranolol; these (p. 408) drugs were judged to be possibly useful but not completely satisfactory (Friedman, 1988). By the middle of the next decade, with the development of the serotonin-selective reuptake inhibitors (SSRIs), antidepressant drugs were drawing increased interest and investigation, though few double-blind clinical trials had been completed at that point (Shalev, Bonne, & Eth, 1996). Concurrently, mood stabilizers, such as lithium, valproate, and carbamazepine were explored for efficacy in PTSD, consequent to observations that the retarded onset of PTSD symptoms greatly resembled the effects of amygdalar kindling, and might best be treated with these antikindling medications (Shalev et al., 1996). This rationale continues to be explored, as discussed below. Within the next 5 years, the weight of expert opinion had settled on the SSRIs as “the best first choice” for PTSD pharmacotherapy (Foa, Davidson, & Frances, 1999). This state of consensus has remained essentially unchanged since then (Ballenger et al., 2000; Balon, 2004; Cooper, Carty, & Creamer, 2005; Cyr & Farrar, 2000; Hageman, Andersen, & Jorgensen, 2001; Pearlstein, 2000). However, this is not to say that the SSRIs are completely satisfactory in all respects. The SSRIs are commended for being well tolerated and having a general efficacy in alleviating most of the symptoms of most victims of PTSD, but problems remain, and the motivation is there to find a wider range of pharmacotherapy solutions. As yet, relatively few well-designed controlled studies have been done with any of the novel potential medications for PTSD. Gender, type of trauma (civilian versus warrelated), severity of PTSD phenomena, and the presence of comorbidities have been identified as relevant factors influencing drug efficacy. Age is a variable that has been largely ignored in the pharmacotherapy literature for PTSD. A very few studies have looked at potential treatments for children and adolescents, but no studies currently on hand have looked at drug treatments for the elderly. Since brain maturation/degeneration and hepatic capacity change over the course of development, age is potentially a very important variable in determining drug effects. And, of course, the issues of dosage, length of treatment, validity of assessment instruments, sample representativeness, random assignment with placebo controls, and including an adequate sample size are relevant to evaluating this line of research, as is true for all research using clinical drug trials.

Antidepressants. The antidepressant medications, particularly various SSRIs, have drawn the most research attention to date (L. L. Davis, English, Ambrose, & Petty, 2001). The first antidepressants to be explored for PTSD efficacy were the MAOIs and tricylics, such as phenelzine, amitriptyline, clomipramine, and imipramine. As a group, these studies tended to use small sample sizes, often without placebo controls, and were highly variable in dosages, measurement scales, and duration of drug treatment (reviewed in J. Davidson et al., 1990). There were common problems with drug intolerance due to side effects. Improvements in PTSD-specific symptoms were usually seen, however, which encouraged the continued search for more effective pharmacotherapy medications among the newer antidepressants, the serotonin-selective reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, and paroxetine.

Exploratory studies (J. Davidson, Roth, & Newman, 1991; McDougle, Southwick, Charney, & St. James, 1991; Nagy, Morgan, Southwick, & Charney, 1993) showed modest but significant improvement with fluoxetine treatment, though it was clear that dosing, duration of treatment, and numerous other factors affecting treatment outcome required further investigation. It was encouraging, however, that fluoxetine was associated with alleviation of the PTSD-specific symptoms, most notably the avoidance/numbing aspect, along with improving depression scale scores. Subsequent random controlled trial studies have provided some support for the efficacy of fluoxetine and a greater understanding of factors that influence treatment success. Source of trauma, time since trauma, and length of drug treatment were raised as issues in a study by van der Kolk and colleagues 1994, when they found that, with 5 weeks of fluoxetine, a civilian sample primarily composed of sexual trauma survivors showed a better treatment response than a sample of military veterans with PTSD of 10 or more years duration. A subsequent study by Hertzberg and colleagues (Hertzberg, Feldman, Beckham, Kudler, & Davidson, 2000) failed to establish efficacy for fluoxetine in a sample of only military veterans after 12 weeks of treatment, while a sample of civilians showed substantial improvement with the same duration of treatment (Connor, Sutherland, Tupler, Malik, & Davidson, 1999). A study by Martenyi and colleagues (Martenyi, Brown, Zhang, Prakash, & Koke, 2002) employed subjects who more recently experienced combat. This group showed substantial improvement in PTSD symptoms after 12 weeks of treatment, suggesting that the older veterans in the Hertzberg and van der Kolk studies were a distinct subject group, possibly having more severe PTSD, or more resistance to treatment due to advanced (p. 409) age or chronicity of PTSD. Another suggestion to emerge from the Martenyi study was that higher doses of fluoxetine may be needed to ameliorate PTSD symptoms than those used to treat depression. Prolonged periods of treatment may also be desirable for fluoxetine to avert relapse of PTSD symptoms (J. R. Davidson et al., 2005; Martenyi, Brown, Zhang, Koke, & Prakash, 2002; Martenyi & Soldatenkova, 2006); however, evidence indicates that fluoxetine is well tolerated and safe for this group (Barnett et al., 2002).

Other SSRI antidepressants have been investigated for efficacy with PTSD. Based on its good treatment record for depression and panic disorder, sertraline was a prime candidate for application to PTSD. The initial controlled trial was very promising; sertraline was particularly effective in reducing PTSD-specific impairments in a civilian sample, had a quick onset of action (improvements were noted within 2 weeks of treatment), and was considered safe and well tolerated (K. Brady et al., 2000). Further randomized clinical trials corroborated this evidence for sertraline as an efficacious drug ameliorating PTSD symptoms (J. R. Davidson, Rothbaum, van der Kolk, Sikes, & Farfel, 2001). Longer-term treatment with sertraline was conducive to continued improvement and prevention of relapse (J. Davidson et al., 2001; Londborg et al., 2001). It was especially noteworthy that efficacy was demonstrated for sertraline with a sample of combat veterans, since fluoxetine was not as successful for treating this population (Zohar et al., 2002). Additional studies have demonstrated a particular reduction in anger soon after sertraline doses are initiated (J. Davidson, Landerman, & Clary, 2004), and an improvement in the comorbid conditions of depression and anxiety (K. T. Brady & Clary, 2003) and excess alcohol consumption (K. T. Brady et al., 2005).

Although fluoxetine showed some efficacy in treating PTSD symptoms, and sertraline more so, both of these medications left room for improvement in sufficiently alleviating all three PTSD symptom clusters. Paroxetine was seen as potentially promising due to its history of success in treating other anxiety disorders as well as depression. Controlled trials from two different groups were, in fact, very encouraging (Marshall, Beebe, Oldham, & Zaninelli, 2001; Tucker et al., 2001). Significant improvement in social and occupational quality of life measures were accompanied by significant reductions on all three PTSD symptom clusters by the end of 12 weeks of treatment in these civilian samples. One analysis indicated that long-term treatment with paroxetine continued to improve PTSD and other anxiety disorder symptoms to the point where the patient could be said to be in remission (Ballenger, 2004).

Sertraline and paroxetine showed convincing evidence for alleviating PTSD symptoms; however, each study contained subjects who failed to respond to the chosen drug. Therefore, as is usually the case with psychopharmacology, other drugs continued to be explored for efficacy. Fluvoxamine has received some research attention but only with small-scale studies without placebo controls. Both a civilian sample (Tucker et al., 2000) and a sample of veterans (Escalona, Canive, Calais, & Davidson, 2002) showed improvement in PTSD symptoms and depression with fluvoxamine; especially noted were improvements in quality of sleep and physiological indexes of arousal (Tucker et al., 2000). However, both studies reported higher dropout rates tied to complaints of side effects when compared to studies using sertraline or fluoxetine.

Preliminary investigations have also been done for the SSRIs citalopram and escitalopram. Escitalopram was efficacious at reducing avoidance/ numbing and hyperarousal symptoms in an open-label trial with a sample of military veterans (Robert, Hamner, Ulmer, Lorberbaum, & Durkalski, 2006), while citalopram improved all symptom clusters in a short-term trial of a similar sample group (English, Jewell, Jewell, Ambrose, & Davis, 2006). It appears that randomized controlled trials (RCT) of these drugs are warranted.

Mirtazapine is a tetracyclic antidepressant with the ability to enhance both 5-HT and NE systems. Three small-scale studies showed evidence of modest to strong improvement in PTSD symptoms in both civilian and military veteran populations (Bahk et al., 2002; Chung et al., 2004; J. R. Davidson et al., 2003; Kim, Pae, Chae, Jun, & Bahk, 2005). The drug was reported to be well tolerated in all three studies, and large-scale randomized controlled trials were felt to be justified by the authors of these studies.

Drugs that promote both NE and 5-HT are beneficial in treating some depression, and may be efficacious for PTSD as well. Nefazodone is a reuptake inhibitor for both 5-HT and NE that is an alternative for treating SSRI nonresponders. A number of studies have provided evidence that this drug is effective in treating PTSD symptoms as well (Garfield, Fichtner, Leveroni, & Mahableshwarkar, 2001), being especially helpful in regulating sleep disturbances (p. 410) and nightmares (J.R.T. Davidson, Weisler, Malik, & Connor, 1998; Gillin et al., 2001; Hertzberg, Feldman, Beckham, Moore, & Davidson, 1998, 2002; Mellman, David, & Barza, 1999; Neylan et al., 2003); however, this drug is associated with some risk of liver failure, which led the manufacturer to pull it from the U.S. market in 2004. Trazodone likewise has effects on 5-HT and NE reuptake but also blocks the 5-HT2 receptor. This drug has antidepressant and sedating qualities and has also shown some efficacy for ameliorating PTSD symptoms, especially sleep dysfunctions (Hertzberg, Feldman, Beckham, & Davidson, 1996; Warner, Dorn, & Peabody, 2001). Venlafaxine is considered a SNRI (5-HT-NE reuptake inhibitor) and has also shown efficacy for reducing scores on CAPS avoidance and hyperarousal scales in a 12-week RCT (J. Davidson, Rothbaum et al., 2006), performing somewhat better at higher doses than sertraline in this sample. Venlafaxine continued to be effective through a 6-month continuation trial, although full remission of PTSD symptoms was not seen (J. Davidson, Baldwin et al., 2006). Although it is at first blush counterintuitive that NE functional agonists should ameliorate PTSD symptoms, since heightened NE activity has been noted in unmedicated PTSD patients (Bremner, Krystal, Southwick, & Charney, 1996), the NE reuptake inhibitor reboxetine was at least as effective as fluvoxamine in ameliorating PTSD symptoms in a small sample of civilian PTSD subjects (Spivak et al., 2006). Also, the NE functional antagonist guanfacine was not found to be helpful in one study (Neylan et al., 2006).

The primary mechanism of action of the antidepressants has been regarded as being the promotion of serotonergic functionality through a number of different receptor-based mechanisms. However, recently a new mechanism of action of the antidepressants has been revealed: these drugs also act to promote neurogenesis in the hippocampus (Huang & Herbert, 2006; Manji et al., 2003; Namestkova, Simonova, & Sykova, 2005; Warner-Schmidt & Duman, 2006). Evidence indicates that the new cells become integrated and functional in memory processes. This recovery of hippocampal tissue is substantial enough to be visualized in the human brain (Vermetten, Vythilingam, Southwick, Charney, & Bremner, 2003). These findings—which await more widespread replication—give some indication that the antidepressant drugs not only ameliorate the symptoms of PTSD, but may also help in the structural recovery of hippocampal tissue that may have been lesioned by exposure to stressors.

Anticonvulsants-Mood Stabilizers. Anticonvulsant drugs have also received investigative interest based on the rationale that the relatively quiescent period between the time of trauma exposure and the occurrence of PTSD symptoms may reflect the operation of a kindling mechanism in the amygdala (Kalynchuk et al., 2006; Kellett & Kokkinidis, 2004) with effects similar to the physical and psychological effects of temporal lobe epilepsy. The anticonvulsant medications are thought to promote gamma-aminobutyric acid (GABA) function; GABA is the predominant inhibitory transmitter in the brain and has traditionally been considered an important element in dysfunctions of fear and anxiety (Nemeroff, 2003). However, not all GABAergic drugs are desirable for treating chronic conditions such as PTSD. The benzodiazepines have been shown to ameliorate some symptoms of PTSD (Shalev, Bloch, Peri, & Bonne, 1998), but run a high risk of tolerance, abuse, and toxic interactions with alcohol. Therefore, drugs having more indirect effects on GABA function, such as the anticonvulsants and mood stabilizers, are more desirable for long-term treatment.

In preliminary uncontrolled studies, carbamazepine and valproate did significantly alleviate PTSD symptoms, especially in the areas of hyperreactivity, sleep disturbance, and intrusive thoughts in small groups of combat veterans (Fesler, 1991; Lipper et al., 1986). Subsequent studies have recognized the efficacy of sertraline and paroxetine as first-line medications, but recognize the need to find other drugs for treatment-resistant patients or as adjunctive therapy for specific problem areas. Lamotrigine is a newer mood stabilizer that is more easily tolerated than the older anticonvulsants; this drug showed evidence for improving the reexperiencing and avoidance clusters in a small sample composed of both civilian and veteran subjects (Hertzberg et al., 1999). Likewise, the GABA agonists levetiracetam, tiagabine, and topiramate have shown some efficacy, with minimal side effects, in small, exploratory investigations (Berlant & van Kammen, 2002; Connor, Davidson, Weisler, Zhang, & Abraham, 2006; Kinrys, Wygant, Pardo, & Melo, 2006). Topiramate (Berlant & van Kammen, 2002) was noted to be especially effective in reducing the reexperiencing cluster, including flashbacks and nightmares, and should be considered for patients with particular difficulties in that area. However, outcomes were more modest for this drug in a RCT of a civilian sample (Tucker et al., 2007). Also in line with these findings, a large (n = 232 subjects) RCT of tiagabine (p. 411) failed to demonstrate its superiority over placebo in the treatment of patients with PTSD (Davidson, Brady, Mellman, Stein, & Pollack, 2007). Phenytoin is also in the anticonvulsant class, but drew attention for efficacy in PTSD because its purported mechanism of action is as a glutamate antagonist. Theoretically, much of the impairment seen in PTSD victims arises from glutamate-mediated hippocampal damage. A glutamate blocker could feasibly act more directly to remedy the symptoms of PTSD in the structures where they are generated. This theoretical approach was supported by findings of significant improvement in all three PTSD clusters in a small mixed sample treated for 3 months with phenytoin (Bremner et al., 2004).

Antipsychotics. A recurring finding through anumber of the studies summarized here has been that the most severe cases of PTSD did not respond to the treatment being offered. At their most extreme expression, the reexperiencing cluster symptoms may take the form of hallucinations and delusions that would be characterized as psychotic. In addition, some PTSD victims have outbursts of anger and aggressiveness that are not very amenable to treatments such as SSRIs. Some researchers have reported the use of antipsychotic medications to address the issues of these more severe cases. This alternative is more attractive now that a number of atypical antipsychotics are available. These drugs generally show fewer side effects, particularly the motor impairments, found with the older antipsychotics. Also, the atypical antipsychotics have effects on 5-HT as well as dopamine systems, and increasing 5-HT functionality is a common route to alleviating PTSD symptoms. Although the first open-label study using olanzapine was disappointing (Butterfield et al., 2001), case reports appeared promising (Jakovljevic, Sagud, & Mihaljevic-Peles, 2003). A second study with a more severely impaired group of military veterans showed very positive results for improvement in PTSD symptoms, especially in the reexperiencing cluster, with few side effects and after only 3 weeks of treatment (Pivac, Kozaric-Kovacic, & Muck-Seler, 2004).

Fluphenazine also alleviated PTSD symptoms but was not tolerated as well (Pivac et al., 2004). Likewise, risperidone was found to be an effective adjunctive medication for alleviating psychotic symptoms, particularly reexperiencing and hyperarousal, in one open-label study (Kozaric-Kovacic, Pivac, Muck-Seler, & Rothbaum, 2005) and four randomized controlled studies (Bartzokis, Lu, Turner, Mintz, & Saunders, 2005; Hamner et al., 2003; Padala et al., 2006; Reich, Winternitz, Hennen, Watts, & Stanculescu, 2004); risperidone may also be appropriate for patients having special difficulties with irritability and heightened aggressiveness (Monnelly, Ciraulo, Knapp, & Keane, 2003). Quetiapine may also be useful as an adjunctive treatment for sleep disorders (Robert et al., 2005) or as an adjunctive therapy for the spectrum of symptoms in those with an unsatisfactory response to other therapies (Ahearn, Mussey, Johnson, Krohn, & Krahn, 2006; Hamner et al., 2003; Sokolski, Denson, Lee, & Reist, 2003). Likewise, current evidence supports the use of olanzapine, and possibly aripiprazole, as potentially helpful adjunctive therapies for PTSD (Lambert, 2006; Stein, Kline, & Matloff, 2002). Finally, there is evidence of the successful use of clozapine in controlling psychotic symptoms in traumatized adolescents (Kant, Chalansani, Chengappa, & Dieringer, 2004; Wheatley, Plant, Reader, Brown, & Cahill, 2004); however, the use of this drug requires consistent monitoring for agranulocytosis, making clozapine a less desirable choice than other atypical antipsychotics.

Future Directions

Some of the more interesting possibilities for interventions with PTSD have come out of our increased understanding of the brain mediation of the processes of learning and memory. In particular, studies on the neural mechanisms and the neurochemistry of extinction of fear learning have begun to show potential for moving into clinical applications.

Extinction is a process of active inhibition of the pathway encoding the conditioned stimulus-unconditioned stimulus (CS-US) association; it occurs after repeated exposure to the CS in the absence of the US. The inhibition is accomplished via GABAergic mechanisms in the basolateral amygdala (Chhatwal, Myers, Ressler, & Davis, 2005). Compelling evidence is accumulating to show that endogenous cannabinoids are required for the GABAergic mechanism of extinction to function. The primary site of action in the brain for the endocannabinoids is the CB1 receptor (Devane, Dysarz, Johnson, Melvin, & Howlett, 1988; Wilson & Nicoll, 2002), which is expressed at high levels in the basolateral amygdala (Chhatwal et al., 2005). In CB1 knockout mice, there is a near-absence of extinction to a fear-conditioned stimulus, and a CB1 antagonist prevents extinction in intact animals (Marsciano et al., 2002). The compound AM404 promotes the neural activity of the endocannabinoids by inhibiting the break (p. 412) down of these molecules and also promotes the course of extinction (Chhatwal, Davis, Maguschak, & Ressler, 2004). If compounds can be developed that are safe for humans and could be taken during exposure therapy, such as reexposure to trauma-associated stimuli with virtual reality, this approach carries the potential of actually “curing” PTSD. This method has already been tried with good results using another extinction promoter, the glutamate partial agonist D-cycloserine, with various anxiety disorders, including PTSD (Heresco-Levy et al., 2002; Hofmann et al., 2006; Ressler et al., 2004). These issues are discussed in more detail in a recent review by Michael Davis and colleagues (M. Davis et al., 2006).

Another line of research indicates that promotion of cannabinoid functionality actually increases the rate of neurogenesis in the hippocampus, as do the SSRI antidepressants, as reviewed above. Rats who show hippocampal neurogenesis after administration of a synthetic cannabinoid also showed reduced anxiety as assessed with a novelty-suppressed feeding paradigm, and reduced depressiveness as assessed with the forced-swim test (Jiang et al., 2005). Findings such as these are opening up new frontiers for the treatment of psychopathologies such as PTSD. We may soon have at our disposal the means to stop PTSD completely in its course, and thereby alleviate a great deal of needless suffering.


Ahearn, E. P., Mussey, M., Johnson, C., Krohn, A., & Krahn, D. (2006). Quetiapine as an adjunctive treatment for posttraumatic stress disorder: An 8-week open-label study. International Clinical Psychopharmacology, 21, 29–33.Find this resource:

    Bahk, W.-M., Pae, C.-U., Tsoh, J., Chae, J.-H., Jun, T.-Y., Kim, C.-L., et al. (2002). Effects of mirtazapine in patients with posttraumatic stress disorder in Korea: A pilot study. Human Psychopharmacology, 17, 341–344.Find this resource:

      Ballenger, J. C. (2004). Remission rates in patients with anxiety disorders treated with paroxetine. Journal of Clinical Psychiatry, 65, 1696–1707.Find this resource:

        Ballenger, J. C., Davidson, J.R.T., Lecrubier, Y., Nutt, D. J., Foa, E. B., Kessler, R. C., et al. (2000). Consensus statement of posttraumatic stress disorder from the international consensus group on depression and anxiety. Journal of Clinical Psychiatry, 61(Suppl. 5), 60–66.Find this resource:

          Balon, R. (2004). Developments in treatment of anxiety disorders: Psychotherapy, pharmacotherapy, and psychosurgery. Depression and Anxiety, 19, 63–76.Find this resource:

            Barnett, S. D., Tharwani, H. M., Hertzberg, M. A., Sutherland, S. M., Connor, K. M., & Davidson, J. R. (2002). Tolerability of fluoxetine in posttraumatic stress disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 26, 363–367.Find this resource:

              Bartzokis, G., Lu, P. H., Turner, J., Mintz, J., & Saunders, C. S. (2005). Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biological Psychiatry, 57, 474–479.Find this resource:

                Berlant, J., & van Kammen, D. P. (2002). Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: A preliminary report. Journal of Clinical Psychiatry, 63, 15–20.Find this resource:

                  Brady, K., Pearlstein, T., Asnis, G. M., Baker, D., Rothbaum, B., Sikes, C. R., et al. (2000). Efficacy and safety of sertraline treatment of posttraumatic stress disorder. Journal of the American Medical Association, 283, 1837–1844.Find this resource:

                    Brady, K. T., & Clary, C. M. (2003). Affective and anxiety comorbidity in posttraumatic stress disorder treatment trials of sertraline. Comprehensive Psychiatry, 44, 360–369.Find this resource:

                      Brady, K. T., Sonne, S., Anton, R. F., Randall, C. L., Back, S. E., & Simpson, K. (2005). Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcoholism: Clinical and Experimental Research, 29, 395–401.Find this resource:

                        Braun, P., Greenberg, D., Dasberg, H., & Lerer, B. (1990). Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. Journal of Clinical Psychiatry, 51, 236–238.Find this resource:

                          Bremner, J. D., Krystal, J. H., Southwick, S. M., & Charney, D. S. (1996). Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse, 23, 39–51.Find this resource:

                            Bremner, J. D., Mletzko, T., Welter, S., Siddiq, S., Reed, L., Williams, C., et al. (2004). Treatment of posttraumatic stress disorder with phenytoin: An open-label pilot study. Journal of Clinical Psychiatry, 65, 1559–1564.Find this resource:

                              Bryant, R. A., Felmingham, K. L., Kemp, A. H., Barton, M., Peduto, A. S., Rennie, C., et al. (2005). Neural networks of information processing in posttraumatic stress disorder: A functional magnetic resonance imaging study. Biological Psychiatry, 58, 111–118.Find this resource:

                                Butterfield, M. I., Becker, M. E., Connor, K. M., Sutherland, S., Churchill, L. E., & Davidson, J.R.T. (2001). Olanzapine in the treatment of posttraumatic stress disorder: A pilot study. International Clinical Psychopharmacology, 16, 197–203.Find this resource:

                                  Chhatwal, J. P., Davis, M., Maguschak, K. A., & Ressler, K. J. (2004). Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychophar-macology, 30, 516–524.Find this resource:

                                    Chhatwal, J. P., Myers, K. M., Ressler, K. J., & Davis, M. (2005). Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquistion and extinction. Journal of Neuroscience, 25, 502–506.Find this resource:

                                      Chung, M. Y., Min, K. H., Jun, Y. J., Kim, S. S., Kim, W. C., & Jun, E. M. (2004). Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: A randomized open label trial. Human Psychopharmacology, 19, 489–494.Find this resource:

                                        Connor, K. M., Davidson, J. R., Weisler, R. H., Zhang, W., & Abraham, K. (2006). Tiagabine for posttraumatic stress disorder: Effects of open-label and double-blind discontinuation treatment. Psychopharmacology, 184, 21–25.Find this resource:

                                          Connor, K. M., Sutherland, S. M., Tupler, L. A., Malik, M. L., & Davidson, J.R.T. (1999). Fluoxetine in posttraumatic stress disorder. British Journal of Psychiatry, 175, 17–23.Find this resource:

                                            Cooper, J., Carty, J., & Creamer, M. (2005). Pharmacotherapy for posttraumatic stress disorder: Empirical review and clinical recommendations. Australian and New Zealand Journal of Psychiatry, 39, 674–682.Find this resource:

                                              Cyr, M., & Farrar, M. K. (2000). Treatment for posttraumatic stress disorder. Annals of Pharmacotherapy, 34, 366–376.Find this resource:

                                                (p. 413) Davidson, J., Baldwin, D., Stein, D. J., Kuper, E., Benattia, I., Ahmed, S., et al. (2006). Treatment of posttraumatic stress disorder with venlafaxine extended release: A 6-month randomized controlled trial. Archives of General Psychiatry, 63, 1158–1165.Find this resource:

                                                  Davidson, J., Kudler, H., Smith, R., Mahorney, S. L., Lipper, S., Hammett, E., et al. (1990). Treatment of posttraumatic stress disorder with amitriptyline and placebo. Archives of General Psychiatry, 47, 259–266.Find this resource:

                                                    Davidson, J., Landerman, L. R., & Clary, C. M. (2004). Improvement of anger at one week predicts the effects of sertraline and placebo in PTSD. Journal of Psychiatric Research, 38, 497–502.Find this resource:

                                                      Davidson, J., Pearlstein, T., Londborg, P., Brady, K. T., Rothbaum, B., Bell, J., et al. (2001). Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: Results of a 28-week double-blind, placebo-controlled study [see comment]. American Journal of Psychiatry, 158, 1974–1981.Find this resource:

                                                        Davidson, J., Roth, S., & Newman, E. (1991). Fluoxetine in posttraumatic stress disorder. Journal of Traumatic Stress, 4, 419–423.Find this resource:

                                                          Davidson, J., Rothbaum, B. O., Tucker, P., Asnis, G., Benattia, I., & Musgnung, J. J. (2006). Venlafaxine extended release in posttraumatic stress disorder: A sertraline-and placebo-controlled study. Journal of Clinical Psychopharmacology, 26, 259–267. [Erratum appears in Journal of Clinical Psychopharmacology, October 2006, 26, 473. Note: dosage error in text.]Find this resource:

                                                            Davidson, J. R. (2006). Pharmacologic treatment of acute and chronic stress following trauma: 2006. Journal of Clinical Psychiatry, 67(Suppl. 2), 34–39.Find this resource:

                                                              Davidson, J. R., Brady, K., Mellman, T. A., Stein, M. B., & Pollack, M. H. (2007). The efficacy and tolerability of tiagabine in adult patients with posttraumatic stress disorder. Journal of Clinical Psychopharmacology, 27, 85–88.Find this resource:

                                                                Davidson, J. R., Connor, K. M., Hertzberg, M. A., Weisler, R. H., Wilson, W. H., & Payne, V. M. (2005). Maintenance therapy with fluoxetine in posttraumatic stress disorder: A placebo-controlled discontinuation study. Journal of Clinical Psychopharmacology, 25, 166–169.Find this resource:

                                                                  Davidson, J. R., Rothbaum, B. O., van der Kolk, B. A., Sikes, C. R., & Farfel, G. M. (2001). Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Archives of General Psychiatry, 58, 485–492.Find this resource:

                                                                    Davidson, J. R., Weisler, R. H., Butterfield, M. I., Casat, C. D., Connor, K. M., Barnett, S., et al. (2003). Mirtazapine vs. placebo in posttraumatic stress disorder: A pilot trial. Biological Psychiatry, 53, 188–191.Find this resource:

                                                                      Davidson, J.R.T., Weisler, R. H., Malik, M. L., & Connor, K. M. (1998). Treatment of posttraumatic stress disorder with nefazodone. International Clinical Psychopharmacology, 13, 111–113.Find this resource:

                                                                        Davis, L. L., English, B. A., Ambrose, S. M., & Petty, F. (2001). Pharmacotherapy for posttraumatic stress disorder: A comprehensive review. Expert Opinion in Pharmacotherapy, 2, 1583–1595.Find this resource:

                                                                          Davis, M. (2000). The role of the amygdala in conditioned and unconditioned fear and anxiety. In J. P. Aggleton (Ed.), The amygdala: A functional analysis (pp. 213–288). Oxford, England: Oxford University Press.Find this resource:

                                                                            Davis, M., Myers, K. M., Chhatwal, J. P., & Ressler, K. J. (2006). Pharmacological treatments that facilitate extinction of fear: Relevance to psychotherapy. NeuroRx: The Journal of the American Society for Experimental Neuro Therapeutics, 3, 82–96.Find this resource:

                                                                              Devane, W. A., Dysarz, F.A.I., Johnson, M. R., Melvin, L. S., & Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology, 34, 605–613.Find this resource:

                                                                                Elsesser, K., Sartory, G., & Tackenberg, A. (2005). Initial symptoms and reactions to trauma-related stimuli and the development of posttraumatic stress disorder. Depression and Anxiety, 21, 61–70.Find this resource:

                                                                                  Elzinga, B. M., & Bremner, J. D. (2002). Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? Journal of Affective Disorders, 70, 1–17.Find this resource:

                                                                                    English, B. A., Jewell, M., Jewell, G., Ambrose, S., & Davis, L. L. (2006). Treatment of chronic posttraumatic stress disorder in combat veterans with citalopram: An open trial. Journal of Clinical Psychopharmacology, 26, 84–88.Find this resource:

                                                                                      Escalona, R., Canive, J. M., Calais, L. A., & Davidson, J. R. (2002). Fluvoxamine treatment in veterans with combat-related posttraumatic stress disorder. Depression and Anxiety, 15, 29–33.Find this resource:

                                                                                        Famularo, R., Kinscherff, R., & Fenton, T. (1988). Propranolol treatment for childhood posttraumatic stress disorder, acute type: A pilot study. American Journal of Diseases of Children, 142, 1244–1247.Find this resource:

                                                                                          Fanselow, M. S., & Poulos, A. M. (2005). The neuroscience of mammalian associative learning. Annual Review of Psychology, 56, 207–234.Find this resource:

                                                                                            Fesler, F. A. (1991). Valproate in combat-related posttraumatic stress disorder. Journal of Clinical Psychiatry, 52, 361–364.Find this resource:

                                                                                              Foa, E. B., Davidson, J.R.T., & Frances, A. (1999). Expert Consensus Guideline Series: Treatment of posttraumatic stress disorder. Journal of Clinical Psychiatry, 60(Suppl. 16), 69–76.Find this resource:

                                                                                                Friedman, M. J. (1988). Toward rational pharmacotherapy for posttraumatic stress disorder: An interim report. American Journal of Psychiatry, 145, 281–284.Find this resource:

                                                                                                  Garfield, D. A., Fichtner, C. G., Leveroni, C., & Mahableshwarkar, A. (2001). Open trial of nefazodone for combat veterans with posttraumatic stress disorder. Journal of Traumatic Stress, 14, 453–460.Find this resource:

                                                                                                    Gelpin, E., Bonne, O., Peri, T., Brandes, D., & Shalev, A. Y. (1996). Treatment of recent trauma survivors with benzodiazepines: A prospective study. Journal of Clinical Psychiatry, 57, 390–394.Find this resource:

                                                                                                      Gillin, J. C., Smith-Vaniz, A., Schnierow, B., Rapaport, M. H., Kelsoe, J., Raimo, E., et al. (2001). An open-label, 12-week clinical and sleep EEG study of nefazodone in chronic combat-related posttraumatic stress disorder. Journal of Clinical Psychiatry, 62, 789–796.Find this resource:

                                                                                                        Hageman, I., Andersen, H. S., & Jorgensen, M. B. (2001). Posttraumatic stress disorder: A review of psychobiology and pharmacotherapy. Acta Psychiatrica Scandinavica, 104, 411–422.Find this resource:

                                                                                                          Hamner, M. B., Faldowski, R. A., Ulmer, H. G., Frueh, B. C., Huber, M. G., & Arana, G. W. (2003). Adjunctive risperidone treatment in posttraumatic stress disorder: A preliminary controlled trial of effects on comorbid psychotic symptoms. International Clinical Psychopharmacology, 18, 1–8.Find this resource:

                                                                                                            Heresco-Levy, U., Kremer, I., Javitt, D. C., Goichman, R., Reshef, A., Blanaru, M., et al. (2002). Pilotcontrolled trial of D-cycloserine for the treatment of posttraumatic stress (p. 414) disorder. International Journal of Neuropsychopharmacology, 5, 301–307.Find this resource:

                                                                                                              Herman, J. P., Figueiredo, H., Mueller, N. K., Ulrich-Lai, Y., Ostrander, M. M., Choi, D. C., et al. (2003). Central mechanisms of stress integration: Hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Frontiers in Neuroendocrinology, 24, 151–180.Find this resource:

                                                                                                                Hertzberg, M. A., Butterfield, M. I., Feldman, M. E., Beckham, J. C., Sutherland, S. M., Connor, K. M., et al. (1999). A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biological Psychiatry, 45, 1226–1229.Find this resource:

                                                                                                                  Hertzberg, M. A., Feldman, M. E., Beckham, J. C., & Davidson, J. R. (1996). Trial of trazodone for posttraumatic stress disorder using a multiple baseline group design. Journal of Clinical Psychopharmacology, 16, 294–298.Find this resource:

                                                                                                                    Hertzberg, M. A., Feldman, M. E., Beckham, J. C., Kudler, H. S., & Davidson, J. R. (2000). Lack of efficacy for fluoxetine in PTSD: A placebo controlled trial in combat veterans. Annals of Clinical Psychiatry, 12, 101–105.Find this resource:

                                                                                                                      Hertzberg, M. A., Feldman, M. E., Beckham, J. C., Moore, S. D., & Davidson, J. R. (1998). Open trial of nefazodone for combat-related posttraumatic stress disorder. Journal of Clinical Psychiatry, 59, 460–464.Find this resource:

                                                                                                                        Hertzberg, M. A., Feldman, M. E., Beckham, J. C., Moore, S. D., & Davidson, J. R. (2002). Three- to four-year follow-up to an open trial of nefazodone for combat-related posttraumatic stress disorder. Annals of Clinical Psychiatry, 14, 215–221.Find this resource:

                                                                                                                          Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., Eisenmenger, K., et al. (2006). Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Archives of General Psychiatry, 63, 298–304.Find this resource:

                                                                                                                            Hoge, C. W., Castro, C. A., Messer, S. C., McGurk, D., Cotting, D. I., & Koffman, R. L. (2004). Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. New England Journal of Medicine, 351, 13–22.Find this resource:

                                                                                                                              Huang, G.-J., & Herbert, J. (2006). Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone. Biological Psychiatry, 59, 619–624.Find this resource:

                                                                                                                                Hurlemann, R., Hawellek, B., Matusch, A., Kolsch, H., Wollersen, H., Madea, B., et al. (2005). Noradrenergic modulation of emotioninduced forgetting and remembering. Journal of Neuroscience, 25, 6343–6349.Find this resource:

                                                                                                                                  Jakovljevic, M., Sagud, M., & Mihaljevic-Peles, A. (2003). Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports. Acta Psychiatrica Scandinavica, 107, 394–396; discussion 396.Find this resource:

                                                                                                                                    Jiang, W., Zhang, Y., Xiao, L., Cleemput, J. V., Ji, S.-P., Bai, G., et al. (2005). Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Journal of Clinical Investigation, 115, 3104–3116.Find this resource:

                                                                                                                                      Kalynchuk, L. E., Pinel, J. P., & Meaney, M. J. (2006). Serotonin receptor binding and mRNA expression in the hippocampus of fearful amygdala-kindled rats. Neuroscience Letters, 396, 38–43.Find this resource:

                                                                                                                                        Kant, R., Chalansani, R., Chengappa, K. N., & Dieringer, M. F. (2004). The off-label use of clozapine in adolescents with bipolar disorder, intermittent explosive disorder, or posttraumatic stress disorder. Journal of Child and Adolescent Psycho-pharmacology, 14, 57–63.Find this resource:

                                                                                                                                          Kellett, J., & Kokkinidis, L. (2004). Extinction deficit and fear reinstatement after electrical stimulation of the amygdala: Implications for kindling-associated fear and anxiety. Neuroscience, 127, 277–287.Find this resource:

                                                                                                                                            Kim, W., Pae, C. U., Chae, J. H., Jun, T. Y., & Bahk, W. M. (2005). The effectiveness of mirtazapine in the treatment of posttraumatic stress disorder: A 24-week continuation therapy. Psychiatry and Clinical Neurosciences, 59, 743–747.Find this resource:

                                                                                                                                              Kinrys, G., Wygant, L. E., Pardo, T. B., & Melo, M. (2006). Levetiracetam for treatment-refractory posttraumatic stress disorder. Journal of Clinical Psychiatry, 67, 211–214.Find this resource:

                                                                                                                                                Kinzie, J. D., & Leung, P. (1989). Clonidine in Cambodian patients with posttraumatic stress disorder. Journal of Nervous and Mental Disease, 177, 546–550.Find this resource:

                                                                                                                                                  Kozaric-Kovacic, D., Pivac, N., Muck-Seler, D., & Rothbaum, B. O. (2005). Risperidone in psychotic combat-related posttraumatic stress disorder: An open trial. Journal of Clinical Psychiatry, 66, 922–927.Find this resource:

                                                                                                                                                    Lambert, M. T. (2006). Aripiprazole in the management of posttraumatic stress disorder symptoms in returning global war on terrorism veterans. International Clinical Psychopharmacology, 21, 185–187.Find this resource:

                                                                                                                                                      Lasiuk, G. C., & Hegadoren, K. M. (2006). Posttraumatic stress disorder part I: Historical development of the concept. Perspectives in Psychiatric Care, 42, 13–20.Find this resource:

                                                                                                                                                        LeDoux, J. (1996). The emotional brain. New York: Simon and Schuster.Find this resource:

                                                                                                                                                          Lipper, S., Davidson, J.R.T., Grady, T. A., Edinger, J. D., Hammett, E. B., Mahorney, S. L., et al. (1986). Preliminary study of carbamazepine in posttraumatic stress disorder. Psychosomatics, 27, 849–854.Find this resource:

                                                                                                                                                            Londborg, P. D., Hegel, M. T., Goldstein, S., Goldstein, D., Himmelhoch, J. M., Maddock, R., et al. (2001). Sertraline treatment of posttraumatic stress disorder: Results of 24 weeks of open-label continuation treatment. Journal of Clinical Psychiatry, 62, 325–331.Find this resource:

                                                                                                                                                              Manji, H. K., Quiroz, J. A., Sporn, J., Payne, J. L., Denicoff, K., Gray, N. A., et al. (2003). Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biological Psychiatry, 53, 707–742.Find this resource:

                                                                                                                                                                Marsciano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, M. G., et al. (2002). The endogenous cannabinoid system controls extinction of aversive memories. Nature, 418, 530–534.Find this resource:

                                                                                                                                                                  Marshall, R. D., Beebe, K. L., Oldham, M., & Zaninelli, R. (2001). Efficacy and safety of paroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study. American Journal of Psychiatry, 158, 1982–1988.Find this resource:

                                                                                                                                                                    Martenyi, F., Brown, E. B., Zhang, H., Koke, S. C., & Prakash, A. (2002). Fluoxetine v. placebo in prevention of relapse in posttraumatic stress disorder [see comment]. British Journal of Psychiatry, 181, 315–320.Find this resource:

                                                                                                                                                                      Martenyi, F., Brown, E. B., Zhang, H., Prakash, A., & Koke, S. C. (2002). Fluoxetine versus placebo in posttraumatic stress disorder. Journal of Clinical Psychiatry, 63, 199–206.Find this resource:

                                                                                                                                                                        Martenyi, F., & Soldatenkova, V. (2006). Fluoxetine in the acute treatment and relapse prevention of combat-related posttraumatic stress disorder: Analysis of the veteran group of a placebo-controlled, randomized clinical trial. European Neuropsychopharmacology, 16, 340–349.Find this resource:

                                                                                                                                                                          McCleery, J. M., & Harvey, A. G. (2004). Integration of psychological and biological approaches to trauma memory: Implications for pharmacological prevention of PTSD. Journal of Traumatic Stress, 17, 485–496.Find this resource:

                                                                                                                                                                            (p. 415) McDougle, C. J., Southwick, S. M., Charney, D. S., & St. James, R. L. (1991). An open trial of fluoxetine in the treatment of posttraumatic stress disorder [letter]. Journal of Clinical Psychiatry, 11, 325–327.Find this resource:

                                                                                                                                                                              McGaugh, J. L. (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience, 27, 1–28.Find this resource:

                                                                                                                                                                                McNally, R. J. (2003). Progress and controversy in the study of posttraumatic stress disorder. Annual Reviews in Psychology, 54, 229–252.Find this resource:

                                                                                                                                                                                  Mellman, T. A., Byers, P. M., & Augenstein, J. S. (1998). Pilot evaluation of hypnotic medication during acute traumatic stress response. Journal of Traumatic Stress, 11, 563–569.Find this resource:

                                                                                                                                                                                    Mellman, T. A., David, D., & Barza, L. (1999). Nefazodone treatment and dream reports in chronic PTSD. Depression and Anxiety, 9, 146–148.Find this resource:

                                                                                                                                                                                      Monnelly, E. P., Ciraulo, D. A., Knapp, C., & Keane, T. (2003). Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder. Journal of Clinical Psychopharmacology, 23, 193–196.Find this resource:

                                                                                                                                                                                        Morgan, C. A., Krystal, J. H., & Southwick, S. M. (2003). Toward early pharmacological posttraumatic stress intervention. Biological Psychiatry, 53, 834–843.Find this resource:

                                                                                                                                                                                          Murchison, C. F., Zhang, X. Y., Zhang, W. P., Ouyang, M., Lee, A., & Thomas, S. A. (2004). A distinct role for norepinephrine in memory retrieval [see comment]. Cell, 117, 131–143.Find this resource:

                                                                                                                                                                                            Nagy, L. M., Morgan, C. A., Southwick, S. M., & Charney, D. S. (1993). Open prospective trial of fluoxetine for posttraumatic stress disorder. Journal of Clinical Psychopharmacology, 13, 107–113.Find this resource:

                                                                                                                                                                                              Namestkova, K., Simonova, Z., & Sykova, E. (2005). Decreased proliferation in the adult rat hippocampus after exposure to the Morris water maze and its reversal by fluoxetine. Behavioural Brain Research, 163, 26–32.Find this resource:

                                                                                                                                                                                                Nemeroff, C. B. (2003). The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacology Bulletin, 37, 133–146.Find this resource:

                                                                                                                                                                                                  Neylan, T. C., Lenoci, M., Maglione, M. L., Rosenlicht, N. Z., Leykin, Y., Metzler, T. J., et al. (2003). The effect of nefazodone on subjective and objective sleep quality in posttraumatic stress disorder. Journal of Clinical Psychiatry, 64, 445–450.Find this resource:

                                                                                                                                                                                                    Neylan, T. C., Lenoci, M., Samuelson, K. W., Metzler, T. J., Henn-Haase, C., Hierholzer, R. W., et al. (2006). No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. American Journal of Psychiatry, 163, 2186–2188.Find this resource:

                                                                                                                                                                                                      Padala, P. R., Madison, J., Monnahan, M., Marcil, W., Price, P., Ramaswamy, S., et al. (2006). Risperidone monotherapy for posttraumatic stress disorder related to sexual assault and domestic abuse in women. International Clinical Psychopharmacology, 21, 275–280.Find this resource:

                                                                                                                                                                                                        Pearlstein, T. (2000). Antidepressant treatment of posttraumatic stress disorder. Journal of Clinical Psychiatry, 61(Suppl. 7), 40–43.Find this resource:

                                                                                                                                                                                                          Phelps, E. A., & LeDoux, J. E. (2005). Contributions of the amygdala to emotion processing: From animal models to human behavior. Neuron, 48, 175–187.Find this resource:

                                                                                                                                                                                                            Pitman, R. K., & Delahanty, D. L. (2005). Conceptually driven pharmacological approaches to acute trauma. CNS Spectrums, 10, 99–106.Find this resource:

                                                                                                                                                                                                              Pitman, R. K., Sanders, K. M., Zusman, R. M., Healy, A. R., Cheema, F., Lasko, N. B., et al. (2002). Pilot study of secondary prevention of posttraumatic stress disorder with propranolol [see comment]. Biological Psychiatry, 51, 189–192.Find this resource:

                                                                                                                                                                                                                Pivac, N., Kozaric-Kovacic, D., & Muck-Seler, D. (2004). Olanzapine versus fluphenazine in an open trial in patients with psychotic combat-related posttraumatic stress disorder. Psychopharmacology, 175, 451–456.Find this resource:

                                                                                                                                                                                                                  Raskind, M. A., Thompson, C., Petrie, E. C., Dobie, D. J., Rein, R. J., Hoff, D. J., et al. (2002). Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. Journal of Clinical Psychiatry, 63, 565–568.Find this resource:

                                                                                                                                                                                                                    Reich, D. B., Winternitz, S., Hennen, J., Watts, T., & Stanculescu, C. (2004). A preliminary study of risperidone in the treatment of posttraumatic stress disorder related to childhood abuse in women. Journal of Clinical Psychiatry, 65, 1601–1606.Find this resource:

                                                                                                                                                                                                                      Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., et al. (2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-Cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry, 61, 1136–1144.Find this resource:

                                                                                                                                                                                                                        Robert, S., Hamner, M. B., Kose, S., Ulmer, H. G., Deitsch, S. E., & Lorberbaum, J. P. (2005). Quetiapine improves sleep disturbances in combat veterans with PTSD: Sleep data from a prospective, open-label study. Journal of Clinical Psychopharmacology, 25, 387–388.Find this resource:

                                                                                                                                                                                                                          Robert, S., Hamner, M. B., Ulmer, H. G., Lorberbaum, J. P., & Durkalski, V. L. (2006). Open-label trial of escitalopram in the treatment of posttraumatic stress disorder. Journal of Clinical Psychiatry, 67, 1522–1526.Find this resource:

                                                                                                                                                                                                                            Rothbaum, B. O., & Davis, M. (2003). Applying learning principles to the treatment of posttrauma reactions. Annals of the New York Academy of Sciences, 1008, 112–121.Find this resource:

                                                                                                                                                                                                                              Shalev, A. Y. (2002). Acute stress reactions in adults. Biological Psychiatry, 51, 532–543.Find this resource:

                                                                                                                                                                                                                                Shalev, A. Y., Bloch, M., Peri, T., & Bonne, O. (1998). Alprazolam reduces response to loud tones in panic disorder but not in posttraumatic stress disorder. Biological Psychiatry, 44, 64–68.Find this resource:

                                                                                                                                                                                                                                  Shalev, A. Y., Bonne, O., & Eth, S. (1996). Treatment of posttraumatic stress disorder: A review. Psychosomatic Medicine, 58, 165–182.Find this resource:

                                                                                                                                                                                                                                    Shalev, A. Y., Freedman, S., Peri, T., Brandes, D., Sahar, T., Orr, S. P., et al. (1998). Prospective study of posttraumatic stress disorder and depression following trauma. American Journal of Psychiatry, 155, 630–637.Find this resource:

                                                                                                                                                                                                                                      Sokolski, K. N., Denson, T. F., Lee, R. T., & Reist, C. (2003). Quetiapine for treatment of refractory symptoms of combat-related posttraumatic stress disorder. Military Medicine, 168, 486–489.Find this resource:

                                                                                                                                                                                                                                        Spivak, B., Strous, R. D., Shaked, G., Shabash, E., Kotler, M., & Weizman, A. (2006). Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: A double-blind, fixed-dosage, controlled trial. Journal of Clinical Psychopharmacology, 26, 152–156.Find this resource:

                                                                                                                                                                                                                                          Stein, M. B., Kline, N. A., & Matloff, J. L. (2002). Adjunctive olanzapine for SSRI-resistant combat-related PTSD: A double-blind, placebo-controlled study [see comment]. American Journal of Psychiatry, 159, 1777–1779.Find this resource:

                                                                                                                                                                                                                                            Taylor, F. B., Lowe, K., Thompson, C., McFall, M. M., Peskind, E. R., Kanter, E. D., et al. (2006). Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biological Psychiatry, 59, 577–581.Find this resource:

                                                                                                                                                                                                                                              (p. 416) Tucker, P., Smith, K. L., Marx, B., Jones, D., Miranda, R., & Lensgraf, J. (2000). Fluvoxamine reduces physiologic reactivity to trauma scripts in posttraumatic stress disorder. Journal of Clinical Psychopharmacology, 20, 367–372.Find this resource:

                                                                                                                                                                                                                                                Tucker, P., Trautman, R. P., Wyatt, D. B., Thompson, J., Wu, S. C., Capece, J. A., et al. (2007). Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: A randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry, 68, 201–206.Find this resource:

                                                                                                                                                                                                                                                  Tucker, P., Zaninelli, R., Yehuda, R., Ruggiero, L., Dillingham, K., & Pitts, C. D. (2001). Paroxetine in the treatment of chronic posttraumatic stress disorder: Results of a placebo-controlled, flexible-dosage trial. Journal of Clinical Psychiatry, 62, 860–868.Find this resource:

                                                                                                                                                                                                                                                    Vaiva, G., Ducrocq, F., Jezequel, K., Averland, B., Lestavel, P., Brunet, A., et al. (2003). Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. [see comment]. Biological Psychiatry, 54, 947–949. [Erratum appears in Biological Psychiatry, December 15, 2003, 54, 1471].Find this resource:

                                                                                                                                                                                                                                                      Van der Kolk, B. A., Dreyfuss, D., Michaels, M., Shera, D., Berkowitz, R., Fisler, R., et al. (1994). Fluoxetine in posttraumatic stress disorder. Journal of Clinical Psychiatry, 55, 517–522.Find this resource:

                                                                                                                                                                                                                                                        Van Praag, H. M. (2004). The cognitive paradox in posttraumatic stress disorder: A hypothesis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28, 923–935.Find this resource:

                                                                                                                                                                                                                                                          Vermetten, E., Vythilingam, M., Southwick, S. M., Charney, D. S., & Bremner, J. D. (2003). Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biological Psychiatry, 54, 693–702.Find this resource:

                                                                                                                                                                                                                                                            Warner, M. D., Dorn, M. R., & Peabody, C. A. (2001). Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares. Pharmacopsychiatry, 34, 128–131.Find this resource:

                                                                                                                                                                                                                                                              Warner-Schmidt, J. L., & Duman, R. S. (2006). Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus, 16, 239–249.Find this resource:

                                                                                                                                                                                                                                                                Wheatley, M., Plant, J., Reader, H., Brown, G., & Cahill, C. (2004). Clozapine treatment of adolescents with posttraumatic stress disorder and psychotic symptoms. Journal of Clinical Psychopharmacology, 24, 167–173.Find this resource:

                                                                                                                                                                                                                                                                  Williams, L. M., Kemp, A. H., Felmingham, K., Barton, M., Olivieri, G., Peduto, A., et al. (2006). Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage, 29, 347–357.Find this resource:

                                                                                                                                                                                                                                                                    Wilson, R. I., & Nicoll, R. A. (2002). Endocannabinoid signaling in the brain. Science, 296, 678–682.Find this resource:

                                                                                                                                                                                                                                                                      Yehuda, R., McFarlane, A. C., & Shalev, A. Y. (1998). Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biological Psychiatry, 44, 1305–1313.Find this resource:

                                                                                                                                                                                                                                                                        Zohar, J., Amital, D., Miodownik, C., Kotler, M., Bleich, A., Lane, R. M., et al. (2002). Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder. Journal of Clinical Psychiatry, 22, 190–195.Find this resource: