The 2023 Veterans Affairs Department of Defense (VA/DoD) guidelines on management of post-traumatic stress disorder (PTSD) suggests against the use of any antipsychotic, including aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone, for augmentation of medications for PTSD, citing very low-quality evidence, small sample sizes, inconsistent efficacy, and a risk-benefit profile in which well-established harms outweigh uncertain benefits. Evidence reviewed showed that risperidone, aripiprazole, and olanzapine were the only agents studied as augmentation, and none demonstrated consistent or statistically significant improvement in overall PTSD outcomes compared with placebo. The 2018 National Institute for Health and Care Excellence (NICE) similarly states that antipsychotics are not first-line treatments for PTSD and should not be considered alternatives to trauma-focused psychological therapies. NICE acknowledges limited evidence suggesting possible symptom improvement with antipsychotics, particularly risperidone, but emphasized that this evidence is weaker than that supporting psychological interventions or antidepressants and lacks long-term follow-up data. Antipsychotics should only be considered as adjunctive therapy for adults with PTSD who have severe, disabling symptoms or psychotic features and who have not responded to other psychological or pharmacological treatments. Given the different side effect profiles, the committee agreed to leave the choice of antipsychotic to clinical judgement. A specialist should perform initiation and management due to tolerability and safety concerns. Both guidelines emphasize that selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have stronger evidence for PTSD than antipsychotics, although neither guideline recommends medication as first-line over trauma-focused psychotherapy. [1], [2]
A 2009 systematic review evaluated non-antidepressant pharmacologic treatments for PTSD in patients who did not respond to or tolerate SSRIs, identifying 63 studies published through October 2008. No antipsychotic reached the highest level of evidence, but risperidone had the strongest support (level B), with 6 randomized controlled trials (RCTs) showing superiority over placebo in several studies primarily as adjunctive therapy, though benefits were inconsistent and did not extend to avoidant behavior or emotional numbness; some trials showed no significant between-group differences, and effects were often limited by small sample sizes and short durations. Olanzapine showed conflicting RCT results, with one adjunctive trial demonstrating significant Clinician Administered PTSD Scale (CAPS) score reductions and sleep improvement over 8 weeks, while a monotherapy trial found no benefit versus placebo; open-label comparative studies with fluphenazine reported symptom reductions but lacked controls. Quetiapine evidence was limited to open-label studies and small case series, with reported reductions in CAPS scores and improvements in sleep and nightmares, corresponding to level C evidence. Clozapine and aripiprazole were supported only by small open-label studies or case series, corresponding to level D evidence, primarily in populations with psychotic features. Overall, the review concluded that antipsychotic evidence for PTSD was limited, heterogeneous, and insufficient to support strong treatment recommendations. See Table 1 for a summary of RCTs of antipsychotics for PTSD included in this review. [3]
A 2018 network meta-analysis of 51 double-blind RCTs (N= 6,189; mean duration 10.3 weeks) evaluated pharmacologic treatments for adult PTSD. Eligible antipsychotics included haloperidol, chlorpromazine, olanzapine, risperidone, and quetiapine, although network estimates were presented only for agents with sufficient placebo-connected randomized data. Among antipsychotics, risperidone was the only agent that demonstrated statistically significant superiority to placebo for symptom reduction, with a standardized mean difference (SMD) of −0.28 (95% confidence interval [CI] −0.54 to −0.01). Olanzapine did not demonstrate a statistically significant effect on PTSD symptom severity versus placebo (SMD −0.51, 95% CI −1.05 to 0.03). For acceptability, no antipsychotic was associated with significantly fewer all-cause dropouts than placebo. Risperidone was associated with higher dropout rates compared with placebo (odds ratio [OR] 1.71, 95% CI 0.72 to 4.04), while olanzapine (OR 1.20, 95% CI 0.42 to 3.43) did not demonstrate significant differences versus placebo. Overall heterogeneity for efficacy was low (τ=0.1; I² 22.4%) and evidence certainty for most antipsychotic comparisons was rated low to very low. [4]
Another meta-analysis of RCTs through June 2019 evaluated pharmacologic treatments for adult PTSD. Atypical antipsychotics as a class demonstrated significant efficacy versus placebo for total PTSD symptom severity (SMD −0.30, 95% CI −0.46 to −0.13). At the individual-drug level, quetiapine (SMD −0.49, 95% CI −0.93 to −0.04), olanzapine (SMD −0.66, 95% CI −1.19 to −0.13), and risperidone (SMD −0.23, 95% CI −0.42 to −0.03) were each superior to placebo for clinician-rated total PTSD symptoms. For re-experiencing symptoms, atypical antipsychotics showed a significant class effect (SMD −0.37, 95% CI −0.54 to −0.19), with significant individual effects reported for quetiapine (SMD −0.53, 95% CI −0.98 to −0.09) and risperidone (SMD −0.36, 95% CI −0.56 to −0.15).For hyperarousal, atypical antipsychotics as a class were effective (SMD −0.37, 95% CI −0.54 to −0.20). Significant individual drug effects were reported for quetiapine (SMD −0.55, 95% CI −1.00 to −0.10) and olanzapine in stratified analyses of severe or extreme PTSD (MD −17.49, 95% CI −32.68 to −2.30). For depressive symptoms, atypical antipsychotics showed a significant class effect (SMD −0.33, 95% CI −0.51 to −0.15). Individual antipsychotics with significant effects included olanzapine (SMD −0.81, 95% CI −1.41 to −0.20) and quetiapine (SMD −0.63, 95% CI −1.08 to −0.18). For anxiety symptoms, atypical antipsychotics demonstrated a significant pooled effect (SMD −0.32, 95% CI −0.51 to −0.12), but no individual antipsychotic-level estimates were reported as statistically significant in the main analyses. For acceptability, atypical antipsychotics did not differ from placebo in all-cause discontinuation, but were associated with a higher risk of discontinuation due to adverse effects (risk ratio [RR] 2.06, 95% CI 1.10 to 3.84). In veteran populations, atypical antipsychotics were the only drug class demonstrating significant efficacy versus placebo (SMD −0.29, 95% CI −0.48 to −0.10), with individual benefits observed for quetiapine (SMD −0.49, 95% CI −0.93 to −0.04) and risperidone (SMD −0.22, 95% CI −0.44 to −0.01). These findings demonstrate patients with different clinical characteristics of PTSD should consider individualized drug management. [5]
Additionally, reviews evaluated RCT evidence for antipsychotics in PTSD. The strongest and most consistent antipsychotic evidence involved risperidone, with small randomized trials demonstrating symptom reduction versus placebo in some populations, including women with non-combat trauma and select veteran cohorts, while other trials, particularly in SSRI-resistant PTSD, showed no benefit. Olanzapine trials produced mixed results, with some studies showing reductions in CAPS scores and sleep symptoms, and others failing to demonstrate superiority to placebo, alongside consistent reports of weight gain and sedation. Evidence for quetiapine, ziprasidone, aripiprazole, and other atypical antipsychotics was limited or absent, largely restricted to uncontrolled studies or prematurely terminated trials. Overall, atypical antipsychotics may show benefit in selected PTSD populations, particularly as augmentation, but findings were inconsistent and constrained by small sample sizes, short treatment durations, heterogeneous trauma types, and frequent concomitant psychotropic use, limiting definitive conclusions. [6], [7]
Newer pharmacologic strategies have been investigated for PTSD. Across three randomized trials, brexpiprazole plus sertraline demonstrated acceptable tolerability but inconsistent efficacy for PTSD. One randomized trial showed greater improvement in PTSD symptoms with the combination compared with sertraline alone, while another similarly designed phase 3 trial failed to demonstrate superiority, with comparable symptom improvement across treatment groups. Earlier phase data suggested potential benefit but were not consistently replicated in subsequent trials. Based on these mixed results, the FDA concluded that the submitted studies did not provide substantial evidence of effectiveness, and issued a Complete Response Letter to the manufacturer stating that additional positive, well-controlled trials would be required for approval. [8], [9], [10], [11]