Efficacy and Harms of Pharmacological Interventions for Anxiety after Traumatic Brain Injury: Systematic Review.

After a traumatic brain injury (TBI), many persons experience significant and debilitating problems with anxiety. The aim of this systematic review was to critically evaluate the evidence regarding efficacy of pharmacological interventions for anxiety after TBI. We reviewed studies published in English before July 2020 and included original research on pharmacological interventions for anxiety after TBI in adults ≥16 years of age. MEDLINE, PubMed, CINAHL, EMBASE, PsycINFO, and CENTRAL databases were searched, with additional searching of key journals, clinical trials registries, and international drug regulators. The primary outcomes of interest were reduction in symptoms of anxiety and occurrence of harms. The secondary outcomes of interest were changes in depression, cognition, quality of life, and participation. Data were summarized in a narrative synthesis, and evidence quality was assessed using the Cochrane Risk of Bias tool. Only a single non-peer-reviewed, randomized controlled trial of 19 male military service members with mild TBI met inclusion criteria. This study found no significant effect of citalopram on anxiety symptoms over a 12-week intervention. The trial was stopped early because of poor recruitment, and much of the study detail was not included in the report. The methodological quality of the study was difficult to assess because of the lack of detail. No recommendations could be drawn from this review. There is a critical need for adequately powered and controlled studies of pharmacological interventions for anxiety after TBI across all severities that examine side-effect profiles and consider issues of comorbidity and effects of long-term pharmacotherapy.

Pharmacotherapy for the Pseudobulbar Affect in Individuals Who Have Sustained a Traumatic Brain Injury: a Systematic Review.

Pseudobulbar affect is a debilitating condition that significantly reduces quality of life for many individuals following traumatic brain injury (TBI). It is characterized by embarrassing and often uncontrollable episodes of crying or laughter. The aim of this systematic review was to evaluate the effectiveness of pharmacotherapy as compared to all other comparators for the management of pseudobulbar affect in adults who have sustained TBI. Six databases were searched, with additional hand searching of journals, clinical trials registries and international drug regulators to identify published and unpublished studies in English up to June 2018. Studies were eligible for this review if they included adults who had sustained a medically confirmed TBI and presented with pseudobulbar affect. All pharmacotherapy and comparator interventions were considered for inclusion, and study design was not limited to randomised controlled trials. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Two quasi-experimental studies examining the effectiveness of dextrometamorphan/quinidine (DM/Q) were identified. These studies reported that DM/Q was effective in reducing symptoms of pseudobulbar affect and had a positive safety profile, over follow-up periods of 3 months (n = 87) and 12 months (n = 23). However, both studies were limited by lack of a control group and a high dropout rate. The findings of twelve case reports examining the effectiveness of DM/Q (n = 6) and anti-depressants (n = 6) are also discussed. Further research is required to determine which pharmacological interventions provide the best outcomes for individuals with pseudobulbar affect following TBI, with consideration given to side effect profiles and financial costs.

The Efficacy and Harms of Pharmacological Interventions for Aggression After Traumatic Brain Injury-Systematic Review.

Background: Aggression is a commonly reported problem following traumatic brain injury (TBI). It may present as verbal insults or outbursts, physical assaults, and/or property destruction. Aggressive behavior can fracture relationships and impede participation in treatment as well as a broad range of vocational and social activities, thereby reducing the individual's quality of life. Pharmacological intervention is frequently used to control aggression following TBI. The aim of this systematic review was to critically evaluate the evidence regarding efficacy of pharmacological interventions for aggression following TBI in adults. Methods: We reviewed studies in English, available before December 2018. MEDLINE, PubMed, CINAHL, EMBASE, PsycINFO, and CENTRAL databases were searched, with additional searching of key journals, clinical trials registries, and international drug regulators. The primary outcomes of interest were reduction in the severity of aggression and occurrence of harms. The secondary outcomes of interest were changes in quality of life, participation, psychological health (e.g., depression, anxiety), and cognitive function. Evidence quality was assessed using the Cochrane Risk of Bias tool and the Joanna Briggs Institute Critical Appraisal Instruments. Results: Ten studies were identified, including five randomized controlled trials (RCTs) and five case series. There were positive, albeit mixed, findings for the RCTs examining the use of amantadine in reducing irritability (n = 2) and aggression (n = 2). There were some positive findings favoring methylphenidate in reducing anger (n = 1). The evidence for propranolol was weak (n = 1). Individual analysis revealed differential drug response across individuals for both methylphenidate and propranolol. The less rigorous studies administered carbamazepine (n = 2), valproic acid (n = 1), quetiapine (n = 1), and sertraline (n = 1), and all reported reductions in aggression. However, given the lack of a control group, it is difficult to discern treatment effects from natural change over time. Conclusions: This review concludes that a recommendation for use of amantadine to treat aggression and irritability in adults following TBI is appropriate. However, there is a need for further well-designed, adequately powered and controlled studies of pharmacological interventions for aggression following TBI.

Prophylaxis Pharmacotherapy to Prevent the Onset of Post-Traumatic Brain Injury Depression: A Systematic Review.

Depression is a common psychiatric problem following traumatic brain injury (TBI) with reported prevalence rates of 30-77% in the first year post-TBI. Given the negative influence of post-TBI depression on cognition and interpersonal, social, physical, and occupational functioning, early initiation of pharmacotherapy to prevent post-TBI depression has been considered. This systematic review will synthesize the available evidence from published studies on the effectiveness and harms of pharmacotherapy for the secondary prevention of post-TBI depression. Studies published prior to October 2018 were eligible for inclusion. Six databases were searched, with additional searching of key additional documents. Studies meeting inclusion criteria were evaluated for methodological quality. Six articles addressing five studies met inclusion criteria. Study designs included three randomized controlled trials (RCTs), two retrospective cohorts, and one case-control. Prophylactic pharmacotherapy included antidepressants, beta-blockers and statins. In one RCT, the number needed to treat with sertraline to prevent one case of depression post-TBI at 24 weeks was 5.9 (95% confidence interval [CI]: 3.1-71.1). In a second RCT affected by significant attrition, sertraline had no effect. Prescribing beta-blockers prior to TBI reduced the depression risk regardless of the specific brain trauma. TBI patients with pre-existing hyperlipidemia not treated with statins had an increased risk for depression compared with those without hyperlipidemia. Overall, this systematic review yielded mixed evidence of prophylactic efficacy and insufficient evidence of harm. In the absence of tolerability data, existing data are insufficient to recommend sertraline prophylaxis. Optimal timing and treatment duration with identification of patients most likely to benefit from prophylaxis require further consideration. Dedicated prospective studies assessing the effects of beta-blockers and statins on post-TBI depression are required.

Efficacy and Harms of Pharmacological Interventions for Neurobehavioral Symptoms in Post-Traumatic Amnesia after Traumatic Brain Injury: A Systematic Review.

Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and amnesia. These symptoms are associated with low rehabilitation engagement, self-inflicted harm, and risk of violence. The aim of this systematic review was to evaluate the efficacy and harms of pharmacological interventions for NBS in PTA following TBI in adults. Studies in English published before December 2017 were reviewed. Six databases were searched, with additional hand searching of key journals, clinical trials registries, and international drug regulators. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Thirteen studies were identified: three randomized controlled trials (RCTs), three cohort studies, and seven case series. In the RCTs, neither amantadine nor sertraline reduced NBS. Less rigorous studies reported reduced NBS in patients administered haloperidol, ziprasidone, carbamazepine, amitriptyline, desipramine, and varied neuroleptics. There is a paucity of well-designed, adequately powered and controlled studies of pharmacological interventions for NBS in PTA. More research is needed to provide evidence-based treatment recommendations and improve care.

Efficacy and harms of pharmacological interventions for neurobehavioral symptoms in post traumatic amnesia after traumatic brain injury: a systematic review and meta-analysis protocol.

REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize the best available evidence on the effectiveness and harms of pharmacotherapy as compared to all types of comparators for the management of neurobehavioral symptoms in post-traumatic amnesia in adults aged 16 years and over who have sustained a traumatic brain injury. This review forms part of a larger project which aims to gather the evidence for the pharmacological treatment of neurobehavioral symptoms post traumatic brain injury as a prelude to the development of a clinical guideline.

Safety and effectiveness of pharmacotherapy for depression in adults who have sustained a traumatic brain injury: a systematic review protocol.

REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize the current evidence on the effectiveness and harms of pharmacotherapy in the management of depression in adults who have sustained a traumatic brain injury.

Who "jumps to conclusions"? A comprehensive assessment of probabilistic reasoning in psychosis following traumatic brain injury (PFTBI), and comparison with TBI, schizophrenia, and nonclinical controls.

INTRODUCTION: The "jumping to conclusions" (JTC) bias has received significant attention in the schizophrenia and delusion literature as an important aspect of cognition characterising psychosis. The JTC bias has not been explored in psychosis following traumatic brain injury (PFTBI). METHODS: JTC was investigated in 10 patients with PFTBI using the beads task (ratios 85:15 and 60:40). Probabilistic predictions, draws-to-decision, self-rated decision confidence, and JTC bias were recorded. Responses from 10 patients with traumatic brain injury (TBI), 23 patients with schizophrenia, and 23 nonclinical controls were compared. Relationships were explored between draws-to-decision and current intelligence quotient, affective state, executive function, delusions (severity and type), and illness chronicity (duration). RESULTS: Groups were comparable on JTC measures. Delusion severity and type were not related to draws-to-decision for either trial. In the entire sample, executive function (reduced mental flexibility) was significantly related to more draws-to-decision on the 60:40 ratio trial. CONCLUSIONS: We found no evidence for an elevated JTC bias in patients with PFTBI or TBI alone. The influence of executive dysfunction should be considered by future studies using the beads tasks in patient populations. These findings need to be replicated in larger PFTBI and TBI samples.

A brief neurocognitive assessment of patients with psychosis following traumatic brain injury (PFTBI): Use of the Repeatable battery for the Assessment of Neuropsychological Status (RBANS).

Patients who develop psychosis following a traumatic brain injury (PFTBI) show impaired neurocognition; however, the degree of impairment has not been empirically investigated using a standardised battery. We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to patients with PFTBI (n=10), and to three groups of controls: traumatic brain injury (TBI) (n=10), schizophrenia (n=23), and nonclinical controls (n=23). The results confirmed that the cognitive neuropsychological profile of dually-diagnosed patients with PFTBI is significantly and substantially impaired. Seventy per cent of patients with PFTBI received a neuropsychological classification between the "extremely low" and "low average" ranges. Group-wise analyses on the RBANS indices indicated that patients with PFTBI had the lowest (Immediate Memory, Attention, Delayed Memory, Total Score), or equal lowest (visuospatial, equivalent with schizophrenia patients) scores, with the exception of the Language Index where no group differences were shown (however, the mean PFTBI score on the Language Index was two standard deviations below the RBANS normative score). These findings provide novel evidence of impaired cognitive neuropsychological processing in patients with PFTBI using a standardised and replicable battery.

Executive dysfunction in psychosis following traumatic brain injury (PFTBI).

INTRODUCTION: Executive dysfunction is well established in patients with traumatic brain injury and in schizophrenia (SCZ). However, assessments of executive function in psychosis following traumatic brain injury (PFTBI) are limited and inconsistent, and often do not reflect the deficits demonstrated in patients with traumatic brain injury (TBI) or SCZ. We sought to determine the extent of executive dysfunction in PFTBI relative to three comparison cohorts. METHOD: Measures of executive function were administered to dually diagnosed patients with PFTBI (n = 10) including tests of mental inhibition and switching, processing speed, and attention: the Stroop Task, Trail Making Test (TMT), and the Attention subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Demographically comparable patients with TBI (n = 10), SCZ (n = 23), and healthy controls (n = 23) underwent an identical battery. RESULTS: Significant executive dysfunction was evident in patients with PFTBI on all measures. Relative to all three comparison cohorts patients with PFTBI performed most poorly. CONCLUSIONS: These data present novel evidence of substantially impaired executive function across four task types in PFTBI and suggest that TBI and psychosis have an additive influence on executive function deficits. Treatment programs requiring substantial executive engagement are not suitable for patients dually diagnosed with PFTBI.

Verbal fluency, clustering, and switching in patients with psychosis following traumatic brain injury (PFTBI).

Verbal fluency in patients with psychosis following traumatic brain injury (PFTBI) has been reported as comparable to healthy participants. This finding is counterintuitive given the prominent fluency impairments demonstrated post-traumatic brain injury (TBI) and in psychotic disorders, e.g. schizophrenia. We investigated phonemic (executive) fluency (3 letters: 'F' 'A' and 'S'), and semantic fluency (1 category: fruits and/or vegetables) in four matched groups; PFTBI (N=10), TBI (N=10), schizophrenia (N=23), and healthy controls (N=23). Words produced (minus perseverations and errors), and clustering and switching scores were compared for the two fluency types across the groups. The results confirmed that PFTBI patients do show impaired fluency, aligned with existing evidence in TBI and schizophrenia. PFTBI patients produced the least amount of words on the phonemic fluency ('A') trial and total score, and demonstrated reduced switching on both phonemic and semantic tasks. No significant differences in clustering performance were found. Importantly, the pattern of results suggested that PFTBI patients share deficits with their brain-injured (primarily executive), and psychotic (executive and semantic), counterparts, and that these are exacerbated by their dual-diagnosis. These findings add to a very limited literature by providing novel evidence of the nature of fluency impairments in dually-diagnosed PFTBI.

Neurophysiological correlates of configural face processing in schizotypy.

BACKGROUND: Face processing impairment in schizophrenia appears to be underpinned by poor configural (as opposed to feature-based) processing; however, few studies have sought to characterize this impairment electrophysiologically. Given the sensitivity of event-related potentials to antipsychotic medications, and the potential for neurophysiological abnormalities to serve as vulnerability markers for schizophrenia, a handful of studies have investigated early visual P100 and face-selective N170 in "at risk" populations. However, this is the first known neurophysiological investigation of configural face processing in a non-clinical schizotypal sample. METHODS: Using stimuli designed to engage configural processing in face perception (upright and inverted Mooney and photographic faces), P100 and N170 components were recorded in healthy individuals characterized by high (N = 14) and low (N = 14) schizotypal traits according to the Oxford-Liverpool Inventory of Feelings and Experiences. RESULTS: High schizotypes showed significantly reduced N170 amplitudes to inverted photographic faces. Typical N170 latency and amplitude inversion effects (delayed and enhanced N170 to inverted relative to upright photographic faces, and enhanced amplitude to upright versus inverted Mooney faces), were demonstrated by low, but not high, schizotypes. No group differences were shown for P100 analyses. CONCLUSIONS: The findings suggest that neurophysiological deficits in processing facial configurations (N170) are apparent in schizotypy, while the early sensory processing (P100) of faces appears intact. This work adds to the mounting evidence for analogous neural processing anomalies at the healthy end of the psychosis continuum.

Impaired semantic memory in the formation and maintenance of delusions post-traumatic brain injury: a new cognitive model of delusions.

This paper proposes a new cognitive model to explain the aetiology of delusions irrespective of diagnosis and/or phenomenology. The model hypothesises the influence of two processes in the formation and maintenance of delusions; (i) impaired perceptual abilities, particularly affect perception, which fosters the encoding of (ii) idiosyncratic semantic memories, especially those with an affective/self-referential valence. Previous research has established that schizophrenia patients with delusions have impaired semantic memory function. In the current paper we sought to provide evidence for (ii) abnormal semantic processing in persons with delusions with an alternative aetiology. Performance of four cases with a significant delusion post a traumatic brain injury was examined on a broad range of semantic memory tests. Overall semantic processing was impaired in the four cases relative to a normative healthy control sample. Cases performed better on tasks which required categorical identification, relative to the novel production of semantic information, which was poor in all four of the cases. These data offer preliminary evidence for our hypothesis of impaired semantic processing in persons with delusions. Findings will need to be empirically verified in larger sample groups and in those with alternative aetiologies.

Elucidating semantic disorganisation from a word comprehension task: do patients with schizophrenia and bipolar disorder show differential processing of nouns, verbs and adjectives?

Memory deficits have been reported in schizophrenia and bipolar disorder. However, the precise impact of semantic memory deficits on word comprehension, particularly across grammatical categories, has not been adequately investigated in these disorders. Furthermore, previous studies examining semantic memory have predominantly been designed so that most healthy controls perform at ceiling, questioning the validity of observed differences between patient and control groups. A new word definition task examined word comprehension across grammatical categories, i.e. nouns, verbs and adjectives, and was designed to overcome the ceiling effect. It was administered to 32 schizophrenia patients, 28 bipolar disorder patients and 32 matched healthy controls. Schizophrenia patients had a global impairment on the task but bipolar patients were only impaired on a recognition memory component. Word comprehension, however, across grammatical categories was comparable across groups.