This article provides a comprehensive understanding of the clinical and conceptual challenges presented by psychosis that is due to TBI.
Table 1. Potential mimics of psychotic symptoms in persons with posttraumatic psychosis
Table 2. Considerations in the differential diagnosis of posttraumatic psychosis
Lindsey Gurin, MD
David B. Arciniegas, MD
Figure 1. Brain MRI of a 60-year-old man presenting with misidentification delusions one year after severe TBI. T2/FLAIR sequence reveals an area of encephalomalacia in the right frontal lobe and T2/FLAIR hyperintensities in the bilateral frontal lobes and right anterior temporal lobe.
Figure 2. Brain MRI of a 23-year-old woman presenting with newonset paranoia four months after a motor vehicle collision in which she suffered significant cervical spinal injury but no obvious head trauma. Susceptibility-weighted imaging sequence revealed chronic microhemorrhages in the bilateral frontal lobes, bilateral anterior temporal lobes, and splenium of the corpus callosum consistent with prior trauma with diffuse axonal injury, confirming a diagnosis of traumatic brain injury.
Premiere Date: April 20, 2019
Expiration Date: October 20, 2020
This activity offers CE credits for:
1. Physicians (CME)
All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.
The goal of this activity is to provide a comprehensive understanding of the clinical and conceptual challenges presented by psychosis that is due to traumatic brain injury (TBI).
At the end of this CE activity, participants should be able to:
• Define the characteristics of posttraumatic psychosis
• Explain the nature of the relationship between TBI and psychosis
• Identify the risk factors for posttraumatic psychosis
• Understand the need for a differential diagnosis when assessing for TBI-related psychosis
• Relate the management strategies for treating TBI-related psychosis
This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.
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Lindsey Gurin, MD, has no disclosures to report.
David B. Arciniegas, MD, reports that he receives royalties from American Psychiatric Association Publishing, Inc, for Neuropsychiatry and Clinical Neurosciences, 6th ed, Textbook of Traumatic Brain Injury, 3rd ed, Journal of Neuropsychiatry and Clinical Neuroscience, as well as royalties from Cambridge University Press for Behavioral Neurology and Neuropsychiatry.
Jonathan Silver, MD (peer/content reviewer), reports that he receives royalties for Textbook of Traumatic Brain Injury, 3rd ed.
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Psychosis after traumatic brain injury (TBI) is a relatively uncommon condition that presents both clinical and conceptual challenges. DSM-5 criteria for Psychotic Disorder due to Another Medical Condition define psychotic disorder due to TBI as delusions or hallucinations that are direct physiologic consequences of TBI; are not better explained by another psychiatric illness or delirium; and cause clinically significant distress or impairment. The requirement for attributing psychosis directly to TBI is often difficult to meet, as the relationship between psychosis and TBI is often multifactorial and rarely permits simple causal attribution.
The cognitive deficits, comorbid medical and neurological problems, and complex pharmacotherapeutic needs and sensitivities of persons with TBI frequently complicate evaluation and treatment of psychosis in this population. In most cases, the development of psychosis in an individual with a history of TBI will be most usefully framed as a psychosis associated with, or after, TBI (ie, posttraumatic psychosis) rather than psychosis due to TBI. Framed as such, relevant differential diagnostic considerations, neurodiagnostic investigations, and evidence-informed management can substantially improve quality of life for patients with posttraumatic psychosis and for their families.
Characteristics of posttraumatic psychosis
DSM-5 guidelines suggest that psychosis due to TBI be considered in a patient with both a history of TBI and psychosis when there is a temporal association between TBI and psychosis and/or when there are atypical features of psychosis present (eg, atypical age of onset or non-auditory hallucinations). In practice, the sometimes-long latency between TBI and the subsequent development of psychosis makes the required temporal association for the diagnosis of psychosis due to TBI difficult to establish. In fact, posttraumatic psychosis demonstrates a bimodal latency period, with a relative minority of patients developing hallucinations and delusions symptoms in the early period after TBI and a larger subset first developing such symptoms years-sometimes decades-after injury, with the mean onset of psychosis after TBI being four to five years.1
Delusions are a core feature of posttraumatic psychosis. The syndrome typically takes one of two forms: delusional disorder, in which delusions are the sole psychotic feature; and schizophrenia-like psychosis, characterized by delusions and hallucinations. Delusional disorder occurs about twice as often as schizophrenia-like psychosis, tends to occur late, and often features misidentification themes.2,3
Schizophrenia-like psychosis after TBI typically features paranoid and persecutory delusions and hallucinations, with grandiose, religious, and external control-related delusions occurring less often. Hallucinations are usually auditory but can occur in other modalities and do so at rates greater than those seen in schizophrenia. Both subtypes are often preceded by a prodrome superimposed on other, usually present, sequelae of TBI; that prodrome is characterized by affective instability, bizarre behavior, performance decline at school or work, social withdrawal, and antisocial behavior. Formal thought disorder and negative symptoms such as affective flattening and avolition are uncommon.
Epidemiologic data on posttraumatic psychosis are mixed. A landmark 1969 review concluded the incidence of psychosis after TBI to be two to three times that of the general population, and modern estimates suggest rates of 0.9% to 8.5%.2,4 A large 2011 meta-analysis estimated a 60% increase in the risk of schizophrenia after TBI compared with the general population.5
Other large-scale studies, however, have failed to show this association, or have shown an increased risk of psychosis that is eliminated after statistically controlling for comorbid substance use disorders.6,7 While a 2011 5-year prospective study showed increased rates of schizophrenia in patients with TBI, a similar 2016 study did not.8,9 The data are likely confounded by inconsistencies across studies with regard to the methods by and rigor with which TBI is assessed:
• Ascertainment bias, particularly ascertainment in clinical/specialty referral populations rather than in community-dwelling populations
• Whether schizophrenia (rather than individual psychotic symptoms) is used as an outcome
• The latency period of psychosis after TBI, which may evade even 5-year observational studies
• The use of family history of psychotic disorders as an inclusion or exclusion criterion
• The probable bidirectional relationship between TBI and psychosis, particularly in multiplex pedigree schizophrenia and bipolar disorder samples
The nature of the relationship between TBI and psychosis is complex and appears to be influenced strongly by patient-specific factors. In some cases, TBI may act as a stressor in a stress-diathesis model of schizophrenia, interacting with underlying genetic susceptibility to produce psychosis. Studies on family history of schizophrenia as a risk factor for psychosis after TBI support this model.10,11 Findings from other studies suggest that TBI may directly induce structural and/or functional brain changes in sensory- and other information-processing networks that manifest with hallucinations and delusions, respectively. Data that show lower rates of familial schizophrenia in patients with posttraumatic psychosis than among patients with schizophrenia without TBI support this model.4,12
Because psychosis itself may engender high-risk behaviors, a “reverse causality” model suggests that psychosis predisposes to TBI rather than vice versa. While pre-TBI rates of psychosis are low-with estimates ranging from 0% to 4.3% and largely accounted for by substance use disorders13-an increased risk of TBI exposure in members of schizophrenia multiplex pedigrees has been seen.10 Higher rates of TBI and other accidental injury in the year preceding the first lifetime admission for schizophrenia suggest that incipient psychosis might predispose to trauma.14
The association between TBI and psychosis may be spurious, driven by independent “psychosis-proneness” factors (eg, perceptual aberrancies, schizotypy, attentional impairments) that increase the likelihood of cerebral trauma and schizophrenia spectrum disorders. Subtle neurological abnormalities are more common among children and adolescents with or at-risk for schizophrenia, even when compared with bipolar controls-potentially predisposing these individuals to accidental injury. Childhood head trauma, which occurs more frequently in schizophrenic patients than in depressive, bipolar, and non-psychiatric controls could be interpreted as a marker of impaired caretaking, with schizophrenic patients placed at higher risk of early TBI merely by virtue of being offspring of parents with schizophrenia.15
Risk factors for posttraumatic psychosis
Younger age at the time of TBI may increase risk of schizophrenia, though these data are mixed. Among individuals diagnosed with posttraumatic psychosis or psychosis due to TBI rather than schizophrenia the age at which TBI occurred does not appear to be a relevant risk factor. Men are at higher risk for posttraumatic psychosis, even when controlling for the baseline increased risk of TBI in men.16 Family history of psychotic disorders is a risk factor for receiving a diagnosis of schizophrenia after TBI, with the risk increased almost threefold in patients in multiplex schizophrenia pedigrees.11 However, posttraumatic psychosis is frequently observed in individuals without a family history of psychotic disorder.
More severe injuries may confer higher risk of posttraumatic psychosis, although schizophrenia studies generally have not shown an association with injury severity. The apparent association of posttraumatic psychosis with more severe TBI and schizophrenia with all injury severities may reflect ascertainment biases; researchers may also be more willing to attribute psychosis to TBI when the occurrence and severity of injury is unequivocal. Left hemisphere-particularly left temporal-injuries are more commonly associated with the schizophrenia-like psychosis form of posttraumatic psychosis; right-sided injuries are more frequently associated with its delusional disorder form. A history of another pre-TBI neurologic disorder may also increase the risk of posttraumatic psychosis.
Nearly 90% of patients with posttraumatic psychosis have cognitive dysfunction attributable to TBI, most typically impairments of attention, language, memory, visuospatial function, and executive function.17,18 Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain is typically abnormal in individuals with posttraumatic psychosis, with frontal and temporal lesions being the most common neuroimaging abnormalities. Electroencephalography (EEG) is abnormal in 70% to 87% of cases; focal temporal and/or frontal slowing is the most common finding, with epileptiform discharges occurring in 27% of schizophrenia-like psychosis and 14% of delusional disorder cases.2
Approach to evaluation
To establish occurrence of a TBI and gauge its severity, inquiry focuses on event-related alterations in consciousness, impaired memory for the injury event (posttraumatic amnesia), and related changes in mental state. The DSM-5 description of Neurocognitive Disorder due to Traumatic Brain Injury provides guidance on the information needed to establish the occurrence of a TBI and gauge its severity (page 626). Readers are encouraged to review and utilize this guidance in their assessment of persons with suspected posttraumatic psychoses.
In addition to determining whether a TBI occurred and, if so, characterizing its severity, the evaluation should seek to identify pre-injury risk factors for posttraumatic psychosis, including neurodevelopmental and psychiatric history, substance use disorders, and family history of psychosis. Careful probing of the weeks and months prior to TBI is essential and can reveal prodromal psychotic symptoms that may have gone unrecognized. The presence of delusions, hallucinations (auditory and otherwise), and negative symptoms should be evaluated, being mindful that negative symptoms may be difficult to parse from post-TBI cognitive dysfunction.
Atypical age of onset and a temporal relationship of psychosis to TBI can be helpful in establishing posttraumatic psychosis. The illness tempo should be elicited, with a paroxysmal course suggesting the possibility of posttraumatic epilepsy. Obtaining collateral information from knowledgeable informants and from the medical record is essential, as posttraumatic cognitive dysfunction, impaired self-awareness, and psychotic symptoms may impede a patient’s ability to serve as a reliable historian.
Mental status examination should evaluate for hallucinations (without insight) and delusions; the character of these symptoms among persons with posttraumatic psychosis is often indistinguishable from those occurring among persons with primary psychotic disorders. The evaluation should also seek to identify formal thought disorder, affective flattening, and negative symptoms, the presence of which is uncommon among individuals with posttraumatic psychoses.
Assessment of attention, processing speed, language, memory, and executive function is essential, and findings must exclude delirium and other potential psychosis mimics (Table 1). Elemental neurological exam should seek to identify focal (especially asymmetric) cranial nerve, motor, sensory, and/or reflex findings consistent with structural brain lesions.
Routine serum laboratory testing should be done to exclude metabolic derangements known to produce delirium or psychotic-like symptoms. Structural neuroimaging should be obtained in all cases of suspected posttraumatic psychosis. MRI is the preferred modality, with T1, T2, fluid-attenuated inversion recovery (FLAIR), and T2* gradient echo (or susceptibility-weighted) sequences (Figures 1 and 2). In most cases, but especially when the history suggests paroxysmal events, EEG should be performed, with consideration of prolonged and/or video-EEG monitoring if the suspicion for posttraumatic epilepsy is high. Neuropsychological testing, which commonly clarifies the nature and extent of cognitive impairments, may help to identify patterns of impairment typical for TBI versus schizophrenia and should also be part of most evaluations.
Psychosis occurring within days or weeks of injury must be distinguished from the posttraumatic confusional state (or delirium), a period of fluctuating disorientation, cognitive impairment, psychomotor restlessness, and sleep/wake disturbance that appears early in the TBI recovery course and can involve transient psychotic symptoms. Delirium due to other causes as well as substance-use disorders (including substance intoxication or withdrawal) must also be excluded. (See Table 2 for a list of considerations in differential diagnosis.)
If mood symptoms are present, diagnoses of mania or depression with psychotic features should be considered, especially if there is a history of premorbid mood disorder. Posttraumatic stress disorder should be considered if the content of symptoms is specific to the trauma event, and careful discrimination between trauma-related symptoms (eg, intrusive thoughts and memories, flashbacks, avoidance) and psychotic symptoms (eg, hallucinations without insight, delusions) is essential.
Schizophrenia should be considered when negative symptoms or formal thought disorder are prominent and when the severity of TBI is mild enough (eg, single, uncomplicated, very remote concussion) so that psychosis is implausibly attributable to it. Isolated hallucinations after TBI are rare and their presence should prompt consideration of other etiologies such as peduncular hallucinosis due to brainstem injury or release phenomena due to vision or hearing loss.
Epilepsy, including posttraumatic epilepsy, can present with ictal, post-ictal, or interictal psychosis. When psychosis occurs in association with posttraumatic epilepsy, a diagnosis of posttraumatic psychosis should be deferred until it is clear that psychotic symptoms persist despite effective seizure control.
Medication-induced psychotic symptoms should also be considered. For example, amantadine, commonly prescribed for cognitive enhancement following severe TBI, may produce hallucinations and delusions in some patients, as can the anticonvulsants levetiracetam and topiramate. Potent anticholinergic and antihistaminergic medications may impair cognition or produce frank delirium, both of which may be mistaken for posttraumatic psychosis. Finally, benzodiazepines may induce paradoxical behavioral disinhibition and delirium that can be mistaken for posttraumatic psychosis.
When psychosis occurs in the setting of mood disorders, substance use disorders (especially substance intoxication or withdrawal), or posttraumatic epilepsy, these should be treated first, and the diagnosis of posttraumatic psychosis deferred until these conditions are effectively treated. If cognitive impairment is prominent and appears to be contributing to information processing abnormalities (eg, delusions), treatment with a cholinesterase inhibitor may improve cognition and secondarily diminish the severity of psychotic symptoms.
The mainstay of treatment for posttraumatic psychosis, however, is antipsychotic medication. When using antipsychotic medications for this purpose, a “start low, go slow-but go” approach is recommended. Initial dosage should be one-half to one-third the usual starting dose with longer intervals between dose adjustments.
Patients with TBI often experience benefits and adverse effects of medications at lower doses and progress should be monitored closely. Symptom control may be achieved at lower doses than are standard for primary psychotic disorders, although standard therapeutic doses are required to effectively treat posttraumatic psychosis. Accordingly, it is important that an empiric trial of antipsychotic medication not be terminated prematurely primarily out of fear of using usual doses of such agents in a patient with a TBI.
Atypical antipsychotics are the preferred pharmacologic treatment for posttraumatic psychosis. We recommend initial treatment with quetiapine in patients with movement disorders given its relatively lower likelihood of producing extrapyramidal effects and cognitive dysfunction, although orthostatic hypotension and, with overly rapid dose escalation, sedation can be treatment-limiting adverse effects. Risperidone is generally effective at doses of 2 to 4 mg, and olanzapine and aripiprazole are also commonly used at doses of 2.5 to 10 mg and 6 to 10 mg, respectively. Chlorpromazine was reported to worsen the condition and produce psychosis after TBI in one case, possibly due to its prominent anticholinergic properties.19
Psychosis after TBI has many potential causes, and the differential diagnosis must be thoroughly considered before attributing psychotic symptoms to TBI. Pharmacotherapy for all forms of psychosis after TBI should take cognitive dysfunction, comorbid illnesses, and the injured brain’s increased sensitivity to medication adverse effects into account, following a “start low, go slow, but go” approach.
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Dr Gurin is Assistant Professor, Departments of Neurology, Psychiatry, and Rehabilitation Medicine, Center for Cognitive Neurology, Pearl I. Barlow Center for Memory Evaluation and Treatment, New York University Langone Medical Center, New York, NY; Dr Arciniegas is Director of Education, Marcus Institute for Brain Health, Clinical Professor of Neurology & Psychiatry, University of Colorado School of Medicine, Physician Research Scientist, Craig Hospital, Englewood, CO.
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