There is growing interest in the use of atypical antipsychotics for the treatment of chronic PTSD. Due to relatively high rates of psychotic features found in more severe PTSD, such as auditory and visual hallucinations and paranoid delusions, this may be a beneficial approach. Several open label trials and RCTs have shown atypical antipsychotic mono-therapy to be a beneficial treatment for PTSD; however, some RCTs have shown no increased benefit compared to placebo (for a detailed review of the literature see Hamner & Robert, 2005). One additional study, not referenced in the Hamner and Robert review (2005), showed 6 weeks of open label treatment with risperidone significantly reduced psychotic symptoms as well as PTSD symptoms for Croatian war Veterans with psychotic PTSD (Kozarić-Kovačić, Pivac, Mück-Šeler, & Rothbaum, 2005).

In addition to positive results as a mono-therapy, there is some research to suggest that atypical antipsychotics work well as adjunctive therapy. For example, Quetiapine has been shown to reduce PTSD and psychotic symptoms when added to a concurrent medication regimen, which included Trazodone, hypnotics, anticonvulsants, and antidepressants, with most patients taking an SSRI (84.2 %) (Hamner, Deitsch et al. 2003). Similar results have been found with risperidone (Hamner, Deitsch et al. 2003; Hamner, Faldowski et al. 2003; Monnelly, Ciraulo, Knapp, & Keane, 2003).

Due to the positive results of general adjunctive therapy with antipsychotics, researchers have examined the effect of augmenting SSRIs specifically with an antipsychotic for the treatment of PTSD. Although SSRIs are the only drugs to be approved by the FDA for the treatment of PTSD, studies indicate a low remission rate for SSRIs as a mono-therapy (e.g., Davidson et al., 2001). There are only a few studies which have examined the addition of an antipsychotic for SSRI non-responders specifically. One study showed two antipsychotics to be beneficial for the treatment of PTSD for individuals who previously failed an SSRI treatment (Pivac & Kozaric-Kovacic, 2004).

There have been two placebo controlled trials examining the augmentation of concurrent SSRI therapy with an antipsychotic for the treatment of PTSD. Stein, Kline, and Matloff (2002) added Olanzepine to ongoing SSRI treatment for combat-related PTSD. Results indicated significantly greater reductions in combat PTSD symptoms, sleep disturbance, and depressive symptoms for the treatment arm as compared to placebo. Rothbaum et al. (2008) examined risperidone augmentation of SSRI therapy for civilian PTSD. In phase I of the trial, individuals were treated for 8 weeks with open label sertraline (Zoloft), an SSRI approved for the treatment of PTSD. Those who did not remit were continued on the sertraline and randomized to 8 weeks of either risperidone or placebo augmentation. Results indicated that all participants, regardless of treatment condition, saw improvement in their PTSD symptoms. More specifically, participants responded well to sertraline in phase 1 and showed a strong placebo response in phase II. Risperidone augmentation did evince beneficial effects in the areas of global improvement and positive affect and sleep. These mixed findings suggest that while atypical antipsychotics are promising as both mono-therapy and adjunctive therapy, more methodologically rigorous studies are required.

A second strategy for treating PTSD looks to correct the shortfalls of medication alone by combining this treatment with the most empirically supported psychotherapy, prolonged exposure (PE) (Foa et al., 2007, 2009). Rothbaum et al. (2006) examined the effect of adding PE for SSRI nonresponders. For this study, individuals diagnosed with PTSD were provided with 10 weeks of open label sertraline therapy and those who did not remit were then randomized to either receive 5 additional weeks of sertraline alone or 5 weeks of sertraline augmented with ten sessions of twice weekly PE. Results showed that the addition of 10 sessions of PE led to increased treatment gains, but only for patients who showed a partial response to phase I sertraline treatment. PE augmentation was associated with lower PTSD severity scores, more remitters at 6 month follow-up, and maintenance of treatment gains.

Simon et al. (2008) examined the mirror design of the Rothbaum et al. (2006) study described above. In phase I of this study, all participants received eight sessions of PE over 4–6 weeks. Those who were still symptomatic at the end of phase I were randomized to receive either continuing PE with an SSRI, paroxetine (Paxil) CR, or placebo. Results showed that paroxetine CR augmentation did not significantly differ from placebo for reduction in PTSD symptoms or severity of illness. It appears from these two studies that exposure therapy can augment SSRI effects, especially for the weaker medication responders (Rothbaum et al., 2006), but that SSRIs do not help boost the response to exposure therapy (Simon et al., 2008). However, a recent double-blind study by Schneier et al. (2012) reports on the combined treatment for 10 weeks using paroxetine and PE simultaneously for 27 adult survivors of the World Trade Center attacks of September 11, 2001 with PTSD. The authors concluded that treatment with combined paroxetine plus PE was more efficacious than PE plus placebo for PTSD both on response and remission rates. After 10 weeks, all patients discontinued PE and were offered 12 more weeks of continued double-blind treatment with paroxetine. The benefit of combined treatment seems to have disappeared by follow-up, with no differences between those on placebo or active treatment at follow-up.

The third augmentation strategy is one in which a medication called d-Cycloserine (DCS) is added to CBT acutely during individual exposure therapy sessions. DCS is an antibiotic which was first developed to treat tuberculosis and has been shown to be a partial agonist of the N-methyl d-aspartate (NMDA) receptor and a potential cognitive enhancer. In order to understand how this augmentation strategy works, it is necessary to briefly discuss the cognitive processes involved in extinction.

Unlike forgetting, extinction requires active learning, which is an NMDA-dependent process. The NMDA receptor mediates intracellular learning processes that lead to cellular changes such as enhanced synaptic activation. Pharmacological agents such as DCS are thought to augment learning processes by improving glutamate neurotransmitter activity at the NMDA receptor. Rodent studies were the first to reveal the effects of DCS on the learning process of fear extinction. Using a classical conditioning paradigm, Walker, Ressler, Lu, and Davis (2002) successfully augmented extinction trials in rodents using DCS. In this paradigm, rodents were first conditioned to fear a light source (conditioned stimulus, or CS) by pairing it with a foot shock (unconditioned stimulus, or UCS), in the fear acquisition phase. Following fear acquisition the rodents underwent extinction training in which the light was presented without the shock 30, 60, or 90 times. Results demonstrated that DCS injections into the amygdala enhanced extinction before 30 non-reinforced light exposures, reaching the level normally achieved after 60 extinction trials. Furthermore, DCS injections did not lead to a reduction in fear for rodents who did not receive extinction training, suggesting that DCS enhances the extinction training but does not independently cause extinction (or sedation). A second rodent study replicated these findings by showing that DCS significantly enhanced the extinction of conditioned fear when administered before extinction training. Furthermore, this study indicated that DCS when administered immediately after extinction training not only influences the acquisition of extinction but also memory consolidation (Ledgerwood, Richardson, & Cranney, 2003). Rodent studies have also revealed a number of additional molecular processes, such as intra-amygdala protein synthesis, which mediate the effect of DCS on extinction (Yang & Lu, 2005) and found that the effect of DCS may be related to the activation of the hippocampal glycinergic system (Yamamoto et al., 2008, 2010). In addition, While DCS seems to increase the efficacy of extinction, it does not have an impact on the renewal effect, or return of fear, when rodents are returned to the context in which fear was acquired (Woods & Bouton, 2006). This finding suggests that while DCS does facilitate extinction learning, the new learning is still dependent on context and the potential for relapse is not necessarily reduced. These rodent studies showed that DCS facilitated amygdala-dependent emotional learning, such as extinction. It is interesting to note that human studies reveal DCS also affects procedural learning. Researchers investigating the effects of DCS during a memory task found that DCS by itself as well as in conjunction with another facilitator of emotional learning, Valproic Acid (VPA), facilitated procedural memory, which was measured by a participant’s ability to rapidly reproduce a series of numbers using a computer keypad. Interestingly, neither cognitive facilitator affected declarative memory, measured by a word pair learning task. The authors determined that this implicates DCS as a hippocampus-independent learning enhancer (Kuriyama, Honma, Koyama, & Kim, 2011).

For clinicians, DCS augmentation of extinction is exciting for a number of reasons. First, it is rational pharmacotherapy, based on what we know about the brain and the extinction of fear. Second, it is a novel paradigm for psychiatric medications. Rather than taken daily or in response to symptoms, DCS is taken only immediately preceding a session of exposure therapy. In the first application to humans described below (Ressler et al., 2004), patients only took two pills in total. The pill does nothing in and of itself (Heresco-Levy et al., 2002), it is only in combination with exposure therapy that it demonstrates its effects. Many patients who enter therapy do not complete a full course of treatment, so anything that makes the therapy that they do receive work faster to achieve more benefits is a huge boost to mental health care.

Initial research studying the effect of DCS augmentation of exposure therapy shows strong support for a number of psychiatric disorders. Specifically, DCS has demonstrated success in treating a variety of anxiety disorders when augmented with exposure therapy (Rothbaum, 2008). Studies included in this review employ a rigorous methodological approach of double-blind, placebo controlled treatment.

Ressler et al. (2004) first studied the effect of DCS augmentation with exposure therapy in humans with the fear of heights. Participants received two sessions of virtual reality exposure therapy (VRE) in conjunction with DCS or placebo. Medication was only taken before each VRE session, for a total of two pills. Results showed significantly greater reductions in acrophobia fears for the DCS group compared to the placebo group in the virtual environment as well as reported real life exposure to heights. The DCS group showed a decrease in spontaneous galvanic skin response (GSR) fluctuation during virtual reality exposure which was related to significantly increased real life exposure to heights after treatment and at 3-month follow-up. These preliminary data demonstrate that acute dosing of DCS can lead to increased benefit from exposure therapy for phobias. Following this study, several investigators around the world have applied the paradigm to other anxiety disorders.

Subsequent research has demonstrated that DCS can lead to increased treatment gains for individuals suffering from social anxiety disorder (SAD). In one study, individuals with a diagnosis of SAD received five exposure therapy sessions, four of which were preceded by a 50 mg dose of DCS or placebo. Results showed that individuals who received DCS compared to placebo before their exposure sessions reported significantly less anxiety symptoms as measured by the Social Phobia and Anxiety Inventory (SPAI—Turner, Beidel, Dancu, & Stanley, 1989) and the Liebowitz Social Anxiety Scale (LSAS- Liebowitz, 1987) at posttreatment and 1 month follow-up (Hofmann et al., 2006). These findings were replicated in Guastella et al. (2008). This study also found significant improvement on measures of dysfunctional cognitions and life impairment associated with SAD for the DCS group in comparison with placebo. Similar results have been found for treatment of panic disorder with 50 mg of DCS administered one hour before three of five sessions (Otto et al., 2010). This study showed DCS augmentation to reduce panic symptoms and produce higher rates of clinically significant change. However, a more recent study found that DCS augmentation did not lead to increased treatment gains for a similar population when given at the same dose and time (Siegmund et al., 2011). The evidence suggests that DCS augmentation with ET may be effective at not only combating the disorder but also at reducing highly impairing symptoms such as negative thoughts or interference with aspects of one’s life such as work, family, and free time.

There have been three double-blind placebo controlled trials of DCS augmentation of ET for obsessive compulsive disorder which have demonstrated mixed results. One study measured OCD symptoms as well as depression symptoms over the course of 10 behavioral therapy sessions (exposure and response prevention). One hour before therapy, patients received either 100 mg of DCS or placebo. Results showed that OCD symptoms were significantly reduced for the DCS group at mid-treatment, but not at posttreatment or 1 month follow-up. Additionally, depression symptoms were reduced at posttreatment but not at midtreatment or follow-up (Wilhelm et al., 2008). A reanalysis of the data from Wilhelm et al. (2008) determined that patients in the DCS group experienced earlier benefits to exposure therapy compared to placebo (Chasson et al., 2010). Another group reported that individuals who received 125 mg of DCS compared to placebo were less likely to drop out and showed significantly greater reductions in symptoms after four sessions of ET. Still, after ten sessions the difference between groups was not significant (Kushner et al., 2007). Coupled with the findings of Wilhelm et al. (2008) and Chasson et al. (2010), this study adds to the theory that DCS may increase the efficacy of ET leading to fewer sessions required to reach the full therapeutic effect. However, Storch et al. (2007) found that there were no significant treatment gains from DCS when individuals with OCD were given a dose of 250 mg of DCS four hours before ET. This study has been criticized for using too large a dose of DCS, too long before the session, and assessing participants only after a full course of ET. Taken together, these studies indicate that the efficacy of DCS augmentation for OCD may be greatest after brief ET (fewer than five sessions) and that dosing should be kept low as well as provided close to treatment (30–60 min prior). In general with DCS in combination with exposure therapy, less is more: lower doses of DCS, given shortly before therapy, and fewer sessions of exposure therapy.

Due to its efficacy in augmenting exposure therapy for a number of different anxiety disorders as well as reducing fear potentiated startle in rodent populations, it stands to reason that DCS could speed the response to exposure therapy for PTSD. Recently, Dr. Barbara Rothbaum has completed a clinical trial at Emory University, in Atlanta, GA, examining the efficacy of DCS augmentation of VRE for PTSD (Rothbaum et al., 2014). Specifically, this treatment provided five sessions of manualized VRE therapy (six sessions total) for Veterans of Iraq and Afghanistan. Thirty minutes prior to each exposure session, participants received either 50 mg of DCS, .25 mg of Alprazolam (Xanax), or placebo. Alprazolam was chosen as an active comparator because it is one of the most common benzodiazepines used in clinical practice for treatment of many anxiety disorders. By providing an “active agent” control in addition to the placebo, this study aimed to directly test the clinical lore that anxiolytic medication interferes with exposure therapy, a finding that may be consistent with preclinical work showing that benzodiazepines actually interfere with extinction of fear in rodents (Bouton, Kenney, & Rosengard, 1990). The results from this type of research design are thus more externally valid since DCS as a new treatment is being tested against existing medication used in the field as opposed to the placebo’s primary use in the laboratory setting.

Results from this study showed that the shortened protocol of VRE successfully reduced symptoms of PTSD in Veterans of the Iraq and Afghanistan wars. However, there was no difference between the DCS group and the placebo group in symptoms of PTSD at any time point. There was a difference between the alprazolam and placebo group in that those receiving alprazolam exhibited greater posttreatment PTSD scores and greater rates of PTSD diagnosis at 3-month follow-up compared to those receiving placebo. While an overall effect of DCS on PTSD symptoms was not found, secondary analyses showed extinction learning between sessions was associated with reduced posttreatment PTSD scores only for those receiving DCS augmentation. Furthermore, DCS was shown to be uniquely related to reduced posttreatment startle response and cortisol reactivity. These findings suggest that alprazolam may inhibit PTSD treatment response and that DCS may be uniquely related to theorized mechanisms of change in PTSD treatment such as, between session extinction learning, cortisol reactivity and startle response.

Five additional trials have reported results of the combination of DCS and CBT for the treatment of PTSD, two with positive findings, two with null findings, and one with negative findings. Henn-Haase et al. (2010) conducted a RCT of exposure-based CBT with DCS or with placebo to investigate DCS’ ability to enhance the effects of exposure therapy in treating PTSD. Both civilian and Veteran patients (n = 28) with full or sub-syndromal PTSD (two of three symptom clusters) on DCS plus exposure therapy reported faster treatment response and greater overall improvements in PTSD symptoms at mid-treatment and posttreatment than those on placebo plus exposure therapy. Similarly, for depression and anxiety symptoms, DCS patients displayed a higher response rate at mid-treatment and posttreatment. Moreover, during the course of treatment sessions, the DCS group reported lower SUDS scores and displayed a greater rate of decrease in SUDS scores. Despite these initial, encouraging findings, the DCS group’s PTSD checklist scores rebounded at 3-month follow-up, suggesting that the effectiveness of DCS is observed primarily during exposure sessions. However, when controlling for pretreatment PTSD symptoms, only the DCS group showed significant improvement in PTSD checklist scores.

In a Canadian trial, 48 civilian patients with PTSD were randomly assigned to CBT + DCS or CBT + placebo (Guay, Marchand, & Landry, 2010). Patients received 12–16 sessions of CBT that included psychoeducation, breathing retraining, imaginal exposure, in vivo exposure, and relapse prevention. From session 4, they received 50 mg of DCS or placebo one hour before each session of imaginal or in vivo exposure. Results indicated that CBT + DCS was not more efficacious than CBT + placebo in decreasing PTSD symptoms on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995) at posttreatment or 6 months following treatment. No mid-treatment or session measures were gathered, so it is not possible to ascertain if there were differences in the speed of response between the groups.

One recent study examined the effect of DCS augmentation on PE for the treatment of noncombat PTSD (de Kleine, Hendriks, Kusters, Broekman, & van Mennen, 2012). In this RCT, patients were administered DCS or placebo 1 h prior to their therapy session. Results indicated that the majority of participants showed significantly reduced CAPS and PTSD Symptom Scale, Self-Report (PSS-SR; Foa, Riggs, Dancu & Rothbaum, 1993) scores at posttreatment and DCS did not significantly impact this reduction. While this study did not find a main effect for DCS on symptom reduction, there was a significantly greater number of responders in the DCS group compared to placebo control. In addition, a session by session analysis revealed that DCS led to greater treatment gains for patients who had higher pretreatment PTSD symptoms and required longer treatment. This was not found for those who completed treatment early. The authors suggested that DCS may be most helpful for those with more severe PTSD and who do not respond as quickly to exposure therapy.

A recently completed RCT (Litz et al., 2012) showed that DCS augmentation of PE led to significantly poorer treatment outcomes on measures of PTSD and depression for combat-related PTSD. This was the first DCS augmentation trial for combat-related PTSD and the first trial to show a negative effect for DCS on treatment outcome. The authors speculated that this unexpected finding may have been the result of the effect DCS has on memory reconsolidation, which is the process by which memories become temporarily labile after being retrieved from long term memory. Furthermore, the sample size of 13 per group was fairly small, thereby limiting power and the ability to find a significant effect. In order to better understand the impact of DCS on combat-related PTSD, additional studies are needed which utilize larger military or veteran samples.

Finally, in a pilot study, Difede et al. (2013) used DCS to augment VRE for PTSD related to the World Trade Center attacks. These results showed that while those receiving DCS did not show significantly reduced symptoms of PTSD compared to placebo immediately posttreatment, they did show reduced symptoms at 6-month follow-up. Furthermore, it was shown that PTSD symptoms began to decline more rapidly for the DCS group compared to the placebo group at session six. PTSD remission rates were greater for those in the DCS group at both posttreatment and 6-month follow-up. Secondary analyses showed the same pattern of response for the DCS groups on measures of depression and anger. Several studies are ongoing comparing DCS to placebo with exposure therapy including one by Drs. Charlie Marmar and Thomas Neylan with Veterans in San Francisco, CA. A 2 × 2 three-site study is just commencing that will compare PE to VRE augmented by DCS or pill placebo using genetic markers as predictors for response to treatment that is being conducted by Drs. Rothbaum, Difede, and Rizzo in the Washington, DC area, New York, and Los Angeles. Finally, a study comparing VRE to PE for active duty Service Members is being conducted by Drs. Greg Gahm and Greg Reger at Joint Fort Lewis McChord in Tacoma, WA. We anxiously anticipate the results of all of these studies to inform us of the utility of these innovations in treatment approaches.