Antipsychotic Use During Posttraumatic Amnesia in Traumatic Brain Injury
Abstract
The present literature review summarizes published studies on posttraumatic amnesia (PTA) outcomes among patients with traumatic brain injury receiving antipsychotics. A PubMed search was conducted with “traumatic brain injury” and “antipsychotic agents” as Medical Subject Headings (MeSH) terms and limited to titles and abstracts (using the tag [tiab]). In the studies reviewed, antipsychotics seemed to help control agitation symptoms during PTA and had varying effects on PTA duration and PTA scores. However, most of the nine articles had observational designs. The efficacy and safety results in the reviewed studies varied and may have been affected by confounding variables. Consequently, research providing high levels of evidence is needed.
Traumatic brain injury (TBI) occurs when an external force disrupts normal brain function. Recovery from TBI involves a progression from loss or alteration of consciousness to appropriate cognitive function. Posttraumatic amnesia (PTA), a transient amnestic state lasting hours to months (depending on TBI severity), may be present during the recovery period (1). Several assessment tools, including the Orientation Log, Galveston Orientation and Amnesia Test, and Westmead Post-Traumatic Amnesia Scale, are used to monitor PTA and determine its resolution (2, 3).
In addition to amnestic symptoms, up to 70% of TBI patients with PTA experience agitation (4, 5). These symptoms may result from disrupted neurocircuitry caused by the injury or may be provoked by sleep-wake cycle disturbances, medical comorbid conditions, and environmental triggers (2, 4, 5). Balancing rehabilitation with harm reduction is essential during PTA, because uncontrolled agitation may prolong hospitalization and hinder recovery (4). TBI practice guidelines promote nonpharmacological interventions, such as environmental modifications or behavioral redirection, as first-line interventions for agitated behavior (1). When pharmacological interventions are needed, beta-blockers and anticonvulsants are recommended; however, guidelines also acknowledge the use of antidepressants, benzodiazepines, stimulants, alpha agonists, N-methyl-d-aspartate antagonists, narcotics, and antipsychotics (2–4).
Antipsychotics are commonly used to treat agitation associated with neuropsychiatric conditions, but caution is recommended when administering them to patients with TBI. Animal studies of controlled cortical impact suggest that D2-dopamine receptor antagonists, when compared with dopamine agonists, may impair cognitive recovery (6). However, direct comparisons are limited due to differences in dosage, administration routes, and underlying causes of agitated neurobehavior between animal and human subjects. Additionally, animal studies cannot assess PTA, which is measured by recording responses to orientation questions (2, 3). PTA is an important prognostic factor, with prolonged duration being associated with longer hospitalizations, higher complication risk, poorer discharge outcomes, and inferior functional recovery at discharge (7, 8).
Although it is suspected that antipsychotics may negatively affect cognition in patients with TBI, their impact on PTA remains unknown (4, 9, 10). If antipsychotics worsen PTA outcomes, then there should be evidence in the literature of changes in PTA duration and symptom severity. Here, we aimed to provide an updated and concise summary of the effects of antipsychotics on PTA.
Methods
After consulting with a medical librarian, a literature review was conducted for English-language articles in PubMed by using the following search terms: (“Brain Injuries, Traumatic”[MeSH] OR traumatic brain injury[tiab] OR traumatic brain injuries[tiab] OR TBI[tiab] OR brain trauma[tiab] OR brain traumas[tiab]) AND (“antipsychotic agents”[Pharmacological Action] OR “antipsychotic agents”[MeSH Terms] OR Antipsychotic[tiab] OR “dopamine antagonists”[Pharmacological Action] OR “dopamine antagonists”[MeSH Terms] OR Dopamine Antagonist[tiab] OR Neuroleptics[tiab]). The inclusion criteria required that articles report efficacy and safety outcomes of antipsychotic use for PTA among patients with TBI of all severities. Additional studies were identified through manual review of the reference lists in the identified articles. No exclusions were made on the basis of study design, publication year, or study location. The administration of any antipsychotic, irrespective of type, route, frequency, or duration of use, was considered. Because the literature is limited, articles with either subjective or objective measurements of agitation control during PTA, PTA scores, and PTA duration were included.
Results
Out of the 212 articles identified in the initial search, six studies met the inclusion criteria (11–16). Through a comprehensive search of the reference lists of these articles and two systematic review articles (4, 9), three additional studies were discovered (17–19). The nine studies that measured PTA outcomes among patients with TBI treated with antipsychotic medications are summarized in Table 1.
| Study | Study type | N | Intervention and outcomes | Key findings |
|---|---|---|---|---|
| Rao et al. (17) | Retrospective observational | 26 | Received or did not receive scheduled haloperidol (dose range: 2–15 mg/day; frequency: not recorded); assessed agitation control during PTA and PTA duration. | 25 of 26 patients had agitated behavior; 11 of 26 required haloperidol. Haloperidol group had resolved agitation but significantly longer PTA duration than nonrecipients (duration: 8 vs. 4 weeks). |
| Maryniak et al. (18) | Retrospective observational | 120 | Received or did not receive scheduled methotrimeprazine (dose range: 2–50 mg; frequency: up to four times daily); assessed agitation control during PTA. | 69 of 120 patients had agitated behavior; 56 of these 69 patients required methotrimeprazine. Agitation was controlled for 54 of 56 methotrimeprazine recipients. |
| Harmsen et al. (11) | Retrospective observational | 60 | Received or did not receive scheduled antipsychotics, including levomepromazine (dose: 25 mg; frequency: daily), haloperidol (dose range 4–8 g; frequency: not recorded), pipamperone (dose: 40 mg; frequency: not recorded), zuclopenthixol and promethazine (dose: 40 and 200 mg; frequency: not recorded), and chlorpromazine (dose: 75 mg; frequency: not recorded); assessed agitation control during PTA. | 28 of 60 patients had PTA at admission; 16 out these 28 patients had positive behavioral disturbances. Odds ratio of developing these disturbances among patients with PTA compared with those without PTA was 41.3; improvements were observed for 7 of 17 patients with positive behavioral disturbances who were prescribed an antipsychotic, which was discontinued within 3 weeks of admission; two patients remained in a state of PTA at the time of discharge. |
| Mysiw et al. (12) | Retrospective observational | 182 | Received narcotics, benzodiazepines, or antipsychotics (type, dose, and frequency: not recorded); patients stratified by those who cleared PTA and those who did not clear PTA; subsequent analyses stratified patients into groups of unknown recipients, recipients, and nonrecipients of benzodiazepines; assessed PTA duration. | 92%, 67%, and 43% of patients were administered narcotics, benzodiazepines, and antipsychotics, respectively. Among unknown and nonrecipients of benzodiazepines, when excluding patients who did not clear PTA, patients receiving narcotics with antipsychotics had a longer period (almost 1 week) of PTA compared with patients receiving narcotics alone. Among benzodiazepine recipients, there was no significant difference in PTA duration between those who received narcotics with antipsychotics and those who received narcotics alone. 11% of patients did not clear PTA during rehabilitation. |
| Noé et al. (13) | Retrospective observational | 37 | TBI patients with PTA at admission who cleared PTA by discharge and received scheduled ziprasidone (dose range 20–80 mg/day; frequency: daily); assessed agitation control during PTA, PTA duration, and ABS scores at baseline and 2 weeks after ziprasidone. | 5 of 37 patients with PTA at admission received ziprasidone. Total ABS mean±SD scores decreased from 27.2±3.0 to 18.0±1.2. Ziprasidone was efficacious in controlling agitation during PTA. Average PTA duration among ziprasidone recipients was 62.4 days, with 100% of ziprasidone recipients clearing PTA. |
| Kooda et al. (19) | Retrospective observational | 195 | Received or did not receive antipsychotics (type, dose, and frequency: not recorded); assessed PTA duration. | 52 of 195 (27%) of patients received antipsychotics within 7 days of TBI (most often quetiapine). 71.7% of antipsychotic recipients also received benzodiazepines (compared with 61% of antipsychotic nonrecipients). PTA duration was significantly longer in the antipsychotic group (mean=19.6 days) than in the no-antipsychotic group (12.3 days). |
| Hammond et al. (14) | Prospective observational | 2,130 | Multicenter study of TBI patients who received antipsychotics (type, dose, and frequency: not recorded); assessed PTA duration. | First-generation antipsychotics used by 11% (N=55), more often as needed than scheduled. Second-generation antipsychotics used by 24% (N=637; 48% quetiapine, 19% risperidone, 15% olanzapine, 14% ziprasidone, 4% aripiprazole, and <1% paliperidone), more often scheduled than as needed. The percentage of patients receiving antipsychotics ranged from 14% to 62% across the 10 study sites. Antipsychotic recipients were more frequently White non-Hispanic males, were 30–45 years old, and had a preinjury psychiatric history and more severe postresuscitation GCS score. Mean PTA duration was 20 days for patients receiving antipsychotics compared with 17, 23, 23, 25, 18, 16, 19, and 23 days for patients receiving anxiolytics, anticonvulsants, antidepressants, antiparkinsonians, hypnotics, narcotic-analgesics, miscellaneous psychotropics, and stimulants, respectively. |
| McKay et al. (15) | Prospective observational | 125 | Received antipsychotic medications (dose and frequency: not recorded); assessed agitation control during PTA and PTA scores before and after dose changes (initiation and discontinuing an antipsychotic; increasing and decreasing the dosage). | Second-generation antipsychotics (olanzapine, quetiapine, and risperidone) were used among one-third (34%, N=42) of patients. No significant difference in ABS scores during initiation or dosage increases. ABS scores improved upon antipsychotic cessation or dosage decrease. PTA (assessed with WPTAS scores) improved in the 3 days after initiation, discontinuation, or increases and decreases in dosage. |
| Phyland et al. (16) | N-of-1 trial | 11 | TBI patients with PTA and agitation received scheduled oral olanzapine (initial dosage of 5 mg/day, titrated every 3 to 4 days to a maximum dosage of 20 mg/day) or placebo; assessed agitation control during PTA, PTA duration, and PTA score. | Patients received oral olanzapine (N=5) or placebo (N=6). No statistically significant between-group differences in ABS score; moderate to large improvements in agitation among 3 of 5 olanzapine recipients (Tau-U effect size=0.37–0.86); longer PTA duration (not statistically significant) among participants receiving olanzapine, with a large effect size (Cohen’s d=1.26); 2 of 6 participants in the placebo group were excluded from the analysis (had not emerged from PTA at the time of publication or PTA duration was >6 months); olanzapine recipients had worse PTA scores compared with placebo recipients, with a large effect size (Cohen’s d=–2.16). |
TABLE 1. Studies measuring posttraumatic amnesia (PTA) outcomes among patients with traumatic brain injury (TBI) treated with antipsychotic medicationsa
Agitation Control During PTA
Six out of nine studies analyzed the use of antipsychotic medications to control agitation during PTA. Both second-generation antipsychotics, such as olanzapine (15, 16) and ziprasidone (13), and first-generation antipsychotics (17–19) were examined. Agitated behavior was assessed subjectively (11, 17, 18) or by using objective measurements, such as the Agitated Behavior Scale (ABS) (13, 15, 16). The frequency and route of medication administration varied among the studies. Five out of six studies involved the initiation of scheduled antipsychotic medications for patients with agitated behavior (11, 13, 16–18), while one study did not specify the dose or frequency of antipsychotics used (15). Studies in which antipsychotics were administered “as needed” were included; however, indications, dosages, and frequencies were not recorded (11, 13, 15–18). Agitation was described as reduced or resolved in five out of six studies (11, 13, 16–18). One study reported reduced agitation (on the basis of ABS scores) following a decrease in dosage or discontinuation of antipsychotic administration (15).
PTA Duration
Six studies examined PTA duration as an outcome among patients with TBI receiving antipsychotic medications (12–14, 16, 17, 19). Among these, only three studies specified which antipsychotic agents were used and at what dose ranges (13, 16, 17). The administration of antipsychotics was associated with varying durations of PTA. Observational studies focusing on haloperidol and ziprasidone showed a significantly prolonged PTA duration (13, 17). In an N-of-1 trial where TBI patients with agitation during PTA were randomly assigned to placebo or olanzapine groups, the olanzapine group appeared to have a longer PTA duration, although this difference did not reach statistical significance (16). Studies that did not specify the type, dose, or frequency of antipsychotics demonstrated variable PTA durations. In a multicenter, prospective observational study, the mean duration of PTA was shorter among antipsychotic recipients than among recipients of anticonvulsants, antidepressants, antiparkinsonian drugs, and stimulants (14).
PTA Score
The effects of antipsychotics on PTA scores was mixed across the reviewed literature. Phyland et al. (16) reported worsened PTA scores for patients receiving olanzapine, whereas McKay et al. (15) described a statistically significant improvement in PTA scores within 3 days of initiating, discontinuing, or adjusting the dosage of any antipsychotic agent.
Discussion
In the broader psychiatric literature, there appears to be favorable safety and efficacy outcomes associated with antipsychotic use for agitated behavior across a range of clinical presentations (20). As such, psychiatrists may be engaged to help manage agitation among patients with TBI, especially during the PTA period. PTA presents challenges to cognitive, functional, and motor recovery after TBI. In this review of the available literature on antipsychotic use during PTA, we identified five studies that reported reduced or resolved agitation. PTA duration varied, with observational studies showing prolonged duration with haloperidol and ziprasidone. One study suggested a longer PTA duration with olanzapine, although the difference was not statistically significant. Studies without a specified antipsychotic agent reported variable PTA durations. The influence of antipsychotics on PTA scores was mixed.
Interpreting the efficacy and safety of antipsychotic medications with the scarce available literature is challenging. The included studies ranged from large multicenter chart reviews to smaller-scale investigations (11–19). Except for one small N-of-1 trial examining the efficacy and safety outcomes of olanzapine (16), most studies were observational. In observational studies without randomization, the comparison of patients who received antipsychotics with those who did not presents risk of selection bias. It is unclear whether outcomes are secondary to deleterious effects of antipsychotics or confounding variables. Additionally, antipsychotic recipients in these studies (compared with nonrecipients) often had more severe injuries and confusion and presented with baseline psychiatric comorbid conditions, making polypharmacy more likely (14).
In the context of agitation control, the influence of changes in dosage remains inconclusive. One study reported reduced agitation (on the basis of ABS scores) following a decrease in dosage or discontinuation of medication; however, it is uncertain whether this change in dosage directly contributed to improved agitation or whether the reduction in agitation was secondary to patients improving and no longer requiring antipsychotic medications (15). The effects of antipsychotic medications on PTA duration and PTA score were unclear, because the available literature did not control for concomitant administration of other psychotropic medications and may have been subject to variability in interrater scoring on assessment scales and measurement protocols (15, 16, 19).
Differentiating between scheduled and as-needed antipsychotic use may reveal differences in total-dose effects. Tailoring dosing for individual patients on the basis of presentation, injury severity, and comorbid conditions may be crucial for future pharmacological management of PTA-associated agitation. However, prescribing antipsychotics in this context involves challenging ethical discussions, because acute safety concerns must be balanced with potential downstream effects of treatment. Future directions may involve randomized controlled trials with scheduled dosing of specific antipsychotic medications with assessments for agitation control, PTA duration, and PTA scores and account for polypharmacy or additional as-needed treatment for breakthrough agitation among antipsychotic recipients compared with nonrecipients.
The present literature review included a comprehensive search for experimental and observational studies. A limitation of this review is the reliance solely on PubMed as a search tool. This resulted in a limited number of studies exploring PTA outcomes among patients with TBI receiving antipsychotics. The scarcity of available experimental studies may be attributable to ethical considerations, given that animal studies suggest negative recovery outcomes among antipsychotic recipients, as well as limited financial resources. Although observational studies have limitations in establishing causation due to potential selection bias and confounding variables, they offer valuable insights into real-world clinical settings and outcomes. The included observational studies provide guidance for researchers in selecting antipsychotic agents, measuring PTA outcomes, and designing studies to control confounding variables.
Conclusion
The literature on the efficacy and safety of antipsychotic use during PTA among patients with TBI is mixed and limited to observational studies and one small experimental trial. Well-designed placebo-controlled randomized clinical trials that account for confounding variables are needed. These types of trials will allow researchers to address the limitations of previous studies and provide more robust evidence regarding the optimal use of antipsychotics in the context of PTA among individuals with TBI.
Key Points/Clinical Pearls
Posttraumatic amnesia (PTA) is a transient alteration in sensorium that is often accompanied by agitation.
Antipsychotic use during PTA is limited by concerns for worsened cognitive outcomes.
Although effects on PTA duration and PTA scores vary, antipsychotic use may improve agitation control during PTA.
The literature is limited to eight observational studies and one small N-of-1 trial; more well-designed experimental studies are needed.
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