Current Psychiatry

The dilemma of a diminishing workforce pool might seem more the province of medical school deans, psychiatry department chairs, and psychiatry residency training directors, but our ability to recruit and retain psychiatrists is, in reality, everyone’s concern—including hospitals, clinics, and, especially, patients and their families. Even without knowledge of the specialty or any numerical appraisal, for example, it is common knowledge that we have a dire shortage of child and adolescent and geriatric psychiatrists—a topic of widespread interest and great consequence for access to mental health care.

Tracking a decline

The very title of a recent provocative paper¹ in Health Affairs says it all: “Population of US practicing psychiatrists declined 2003-13, which may help explain poor access to mental health care.” In an elegant analysis, the authors expose (1) a 10% decline in the number of psychiatrists for every 100,000 people and (2) wide regional variability in the availability of psychiatrists. In stark contrast, the number of neurologists increased by >15% and the primary care workforce remained stable, with a 1.3% increase in the number of physicians, over the same 10 years.

At the beginning of the psychiatry workforce pipeline, the number of medical students who choose psychiatry remains both small (typically, slightly more than 4% of graduating students) and remarkably stable over time. Wilbanks et al,² in a thoughtful analysis of the 2011 to 2013 Medical School Graduation Questionnaire of the Association of American Medical Colleges, affirm and, in part, explain this consistent pattern. They note that the 4 most important considerations among students who select psychiatry are:

• personality fit
• specialty content
• work–life balance
• role model influences.

Some of these considerations also overlap with those of students in other specialties; the authors also note that older medical students and women are more likely to choose psychiatry.

Here is what we must do to erase the shortage

It does appear that, despite scientific advances in brain and behavior, expanding therapeutic options, and unique patient interactions that, taken together, should make a career in psychiatry exciting and appealing, there are simply not enough of us to meet the population’s mental health needs. This is a serious problem. It is our professional obligation—all of us—that we take on this shortage and develop solutions to it.

At its zenith, only about 7% of medical students chose psychiatry. We need to proactively prime the pump for our specialty by encouraging more observerships and promoting mental health careers through community outreach to high school students.

We must be diligent and effective mentors to medical students; mentorship is a powerful catalyst for career decision-making.

We need to make psychiatry clerkships exciting, to show off the best of what our specialty has to offer, and to cultivate sustained interest among our students in the brain and its psychiatric disorders.

We need to highlight the momentous advances in knowledge, biology, and treatments that now characterize our psychiatric profession. We need to advocate for more of these accomplishments.

We must be public stigma-busters! (Our patients need us to do this, too.)

And there is more to do:

Collaborate. In delivering psychiatric health care, we need to expand our effectiveness to achieve more collaboration, greater extension of effect, and broader outreach. Collaborative care has come of age as a delivery model; it should be embraced more broadly. We need to continue our efforts to bridge the many sister mental health disciplines—psychology, nursing, social work, counseling—that collectively provide mental health care.

Unite. Given the inadequate workforce numbers and enormous need, we will diminish ourselves by “guild infighting” and, consequently, weaken our legislative advocacy and leverage. We need to embrace and support all medical specialties and have them support us as well. We need to grow closer to primary care and support this specialty as the true front line of mental health. We also need to bridge the gap between addiction medicine and psychiatry, especially given the high level of addiction comorbidity in many psychiatric disorders.

Foster innovation. The deficit of psychiatric workers might be buffered by innovations in how we leverage our expertise. Telepsychiatry, for example, is clearly advancing, and brings psychiatry to remote areas where psychiatrists are scarce. Mobile health also has great potential for mental health. As one of us (H.A.N.) highlighted recently,³ as genetics become more molecular, what has been the potential of clinically applicable pharmacogenomics might become reality. Psychiatry needs to make progress toward personalized medicine because the disorders we treat are extremely heterogeneous in their etiology, phenomenology, treatment response, and outcomes.

The appeal of working with mind and brain

The extent to which we can convey unfettered optimism about the role of psychiatry in medicine and the relentless progress in neurobiological research, together, will go a long way toward attracting the best and brightest newly minted physicians to our specialty. The brain is the last frontier in medicine; psychiatry is intimately tethered to its unfolding complexity. With millennials placing a higher premium on work–life issues, the enviable balance and quality of life of a psychiatric career might now be particularly opportune, enhancing the quantity and quality of professionals that we can attract to psychiatry.
 

The dilemma of a diminishing workforce pool might seem more the province of medical school deans, psychiatry department chairs, and psychiatry residency training directors, but our ability to recruit and retain psychiatrists is, in reality, everyone’s concern—including hospitals, clinics, and, especially, patients and their families. Even without knowledge of the specialty or any numerical appraisal, for example, it is common knowledge that we have a dire shortage of child and adolescent and geriatric psychiatrists—a topic of widespread interest and great consequence for access to mental health care.

Tracking a decline

The very title of a recent provocative paper¹ in Health Affairs says it all: “Population of US practicing psychiatrists declined 2003-13, which may help explain poor access to mental health care.” In an elegant analysis, the authors expose (1) a 10% decline in the number of psychiatrists for every 100,000 people and (2) wide regional variability in the availability of psychiatrists. In stark contrast, the number of neurologists increased by >15% and the primary care workforce remained stable, with a 1.3% increase in the number of physicians, over the same 10 years.

At the beginning of the psychiatry workforce pipeline, the number of medical students who choose psychiatry remains both small (typically, slightly more than 4% of graduating students) and remarkably stable over time. Wilbanks et al,² in a thoughtful analysis of the 2011 to 2013 Medical School Graduation Questionnaire of the Association of American Medical Colleges, affirm and, in part, explain this consistent pattern. They note that the 4 most important considerations among students who select psychiatry are:

• personality fit
• specialty content
• work–life balance
• role model influences.

Some of these considerations also overlap with those of students in other specialties; the authors also note that older medical students and women are more likely to choose psychiatry.

Here is what we must do to erase the shortage

It does appear that, despite scientific advances in brain and behavior, expanding therapeutic options, and unique patient interactions that, taken together, should make a career in psychiatry exciting and appealing, there are simply not enough of us to meet the population’s mental health needs. This is a serious problem. It is our professional obligation—all of us—that we take on this shortage and develop solutions to it.

At its zenith, only about 7% of medical students chose psychiatry. We need to proactively prime the pump for our specialty by encouraging more observerships and promoting mental health careers through community outreach to high school students.

We must be diligent and effective mentors to medical students; mentorship is a powerful catalyst for career decision-making.

We need to make psychiatry clerkships exciting, to show off the best of what our specialty has to offer, and to cultivate sustained interest among our students in the brain and its psychiatric disorders.

We need to highlight the momentous advances in knowledge, biology, and treatments that now characterize our psychiatric profession. We need to advocate for more of these accomplishments.

We must be public stigma-busters! (Our patients need us to do this, too.)

And there is more to do:

Collaborate. In delivering psychiatric health care, we need to expand our effectiveness to achieve more collaboration, greater extension of effect, and broader outreach. Collaborative care has come of age as a delivery model; it should be embraced more broadly. We need to continue our efforts to bridge the many sister mental health disciplines—psychology, nursing, social work, counseling—that collectively provide mental health care.

Unite. Given the inadequate workforce numbers and enormous need, we will diminish ourselves by “guild infighting” and, consequently, weaken our legislative advocacy and leverage. We need to embrace and support all medical specialties and have them support us as well. We need to grow closer to primary care and support this specialty as the true front line of mental health. We also need to bridge the gap between addiction medicine and psychiatry, especially given the high level of addiction comorbidity in many psychiatric disorders.

Foster innovation. The deficit of psychiatric workers might be buffered by innovations in how we leverage our expertise. Telepsychiatry, for example, is clearly advancing, and brings psychiatry to remote areas where psychiatrists are scarce. Mobile health also has great potential for mental health. As one of us (H.A.N.) highlighted recently,³ as genetics become more molecular, what has been the potential of clinically applicable pharmacogenomics might become reality. Psychiatry needs to make progress toward personalized medicine because the disorders we treat are extremely heterogeneous in their etiology, phenomenology, treatment response, and outcomes.

The appeal of working with mind and brain

The extent to which we can convey unfettered optimism about the role of psychiatry in medicine and the relentless progress in neurobiological research, together, will go a long way toward attracting the best and brightest newly minted physicians to our specialty. The brain is the last frontier in medicine; psychiatry is intimately tethered to its unfolding complexity. With millennials placing a higher premium on work–life issues, the enviable balance and quality of life of a psychiatric career might now be particularly opportune, enhancing the quantity and quality of professionals that we can attract to psychiatry.
 

The dilemma of a diminishing workforce pool might seem more the province of medical school deans, psychiatry department chairs, and psychiatry residency training directors, but our ability to recruit and retain psychiatrists is, in reality, everyone’s concern—including hospitals, clinics, and, especially, patients and their families. Even without knowledge of the specialty or any numerical appraisal, for example, it is common knowledge that we have a dire shortage of child and adolescent and geriatric psychiatrists—a topic of widespread interest and great consequence for access to mental health care.

Tracking a decline

The very title of a recent provocative paper¹ in Health Affairs says it all: “Population of US practicing psychiatrists declined 2003-13, which may help explain poor access to mental health care.” In an elegant analysis, the authors expose (1) a 10% decline in the number of psychiatrists for every 100,000 people and (2) wide regional variability in the availability of psychiatrists. In stark contrast, the number of neurologists increased by >15% and the primary care workforce remained stable, with a 1.3% increase in the number of physicians, over the same 10 years.

At the beginning of the psychiatry workforce pipeline, the number of medical students who choose psychiatry remains both small (typically, slightly more than 4% of graduating students) and remarkably stable over time. Wilbanks et al,² in a thoughtful analysis of the 2011 to 2013 Medical School Graduation Questionnaire of the Association of American Medical Colleges, affirm and, in part, explain this consistent pattern. They note that the 4 most important considerations among students who select psychiatry are:

• personality fit
• specialty content
• work–life balance
• role model influences.

Some of these considerations also overlap with those of students in other specialties; the authors also note that older medical students and women are more likely to choose psychiatry.

Here is what we must do to erase the shortage

It does appear that, despite scientific advances in brain and behavior, expanding therapeutic options, and unique patient interactions that, taken together, should make a career in psychiatry exciting and appealing, there are simply not enough of us to meet the population’s mental health needs. This is a serious problem. It is our professional obligation—all of us—that we take on this shortage and develop solutions to it.

At its zenith, only about 7% of medical students chose psychiatry. We need to proactively prime the pump for our specialty by encouraging more observerships and promoting mental health careers through community outreach to high school students.

We must be diligent and effective mentors to medical students; mentorship is a powerful catalyst for career decision-making.

We need to make psychiatry clerkships exciting, to show off the best of what our specialty has to offer, and to cultivate sustained interest among our students in the brain and its psychiatric disorders.

We need to highlight the momentous advances in knowledge, biology, and treatments that now characterize our psychiatric profession. We need to advocate for more of these accomplishments.

We must be public stigma-busters! (Our patients need us to do this, too.)

And there is more to do:

Collaborate. In delivering psychiatric health care, we need to expand our effectiveness to achieve more collaboration, greater extension of effect, and broader outreach. Collaborative care has come of age as a delivery model; it should be embraced more broadly. We need to continue our efforts to bridge the many sister mental health disciplines—psychology, nursing, social work, counseling—that collectively provide mental health care.

Unite. Given the inadequate workforce numbers and enormous need, we will diminish ourselves by “guild infighting” and, consequently, weaken our legislative advocacy and leverage. We need to embrace and support all medical specialties and have them support us as well. We need to grow closer to primary care and support this specialty as the true front line of mental health. We also need to bridge the gap between addiction medicine and psychiatry, especially given the high level of addiction comorbidity in many psychiatric disorders.

Foster innovation. The deficit of psychiatric workers might be buffered by innovations in how we leverage our expertise. Telepsychiatry, for example, is clearly advancing, and brings psychiatry to remote areas where psychiatrists are scarce. Mobile health also has great potential for mental health. As one of us (H.A.N.) highlighted recently,³ as genetics become more molecular, what has been the potential of clinically applicable pharmacogenomics might become reality. Psychiatry needs to make progress toward personalized medicine because the disorders we treat are extremely heterogeneous in their etiology, phenomenology, treatment response, and outcomes.

The appeal of working with mind and brain

The extent to which we can convey unfettered optimism about the role of psychiatry in medicine and the relentless progress in neurobiological research, together, will go a long way toward attracting the best and brightest newly minted physicians to our specialty. The brain is the last frontier in medicine; psychiatry is intimately tethered to its unfolding complexity. With millennials placing a higher premium on work–life issues, the enviable balance and quality of life of a psychiatric career might now be particularly opportune, enhancing the quantity and quality of professionals that we can attract to psychiatry.
 

The first 15 years of the new millennium have seen a great increase in research on neuroimaging in children and adolescents who have a psychiatric disorder. In addition, imaging modalities continue to evolve, and are becoming increasingly accessible and informative. The literature is now replete with reports of neurostructural differences between patients and healthy subjects in a variety of common pediatric psychiatric conditions, including anxiety disorders, mood disorders, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD).

Historically, the clinical utility of neuroimaging was restricted to the identification of structural pathology. Today, accumulating data reveal novel roles for neuroimaging; these revelations are supported by studies demonstrating that treatment response for psychotherapeutic and psychopharmacotherapeutic interventions can be predicted by neuro­chemical and neurofunctional characteristics assessed by advanced imaging technologies, such as magnetic resonance spectroscopy (MRS) and functional MRI.

However, such advanced techniques are (at least at present) not ready for routine clinical use for this purpose. Instead, neuroimaging in the child and adolescent psychiatric clinic remains largely focused on ruling out neurostructural, neurologic, “nonpsychiatric” causes of our patients’ symptoms.

Understanding the role and limitations of major imaging modalities is key to guiding efficient and appropriate neuroimaging selection for pediatric patients. In this article, we describe and review:

• neuroimaging approaches for children and adolescents with psychiatric disorders
• the role of neuroimaging in (1) the differential diagnosis and workup of common psychiatric disorders and (2) urgent clinical situations
• how to determine what type of imaging to obtain.

Computed tomography

CT, which utilizes ionizing radiation, often is reserved, in the pediatric setting, for (1) emergency evaluation and (2) excluding potentially catastrophic neurologic injury resulting from:

• ischemic or hemorrhagic stroke
• herniation
• intracerebral hemorrhage
• subdural and epidural hematoma
• large intracranial mass with mass effect
• increased intracranial pressure
• acute skull fracture.

Although a CT scan is, typically, quick and has excellent sensitivity for acute bleeding and bony pathology, it exposes the patient to radiation and provides poor resolution compared with MRI.

In pediatrics, there has been practice-changing recognition of the importance of limiting lifetime radiation exposure incurred from medical procedures and imaging. As a result, most providers now agree that use of MRI in lieu of CT is appropriate in many, if not most, non-emergent situations. In an emergent situation, however, CT imaging is appropriate and should not be delayed. Moreover, in an emergent situation, you should not hesitate to use head CT in children, although timely discussion with the radiologist is recommended to review your differential diagnosis to better determine the preferred imaging modality.

Magnetic resonance imaging

Over the past several decades, MRI has been increasingly available in most pediatric health care facilities. The modality offers specific advantages for pediatric patients, including:

• better spatial resolution
• the ability to concurrently assess multiple pathologic processes
• lack of exposure to ionizing radiation.¹

A number of MRI sequences, described below, can be used to assess vascular, inflammatory, structural, and metabolic processes.

A look inside. Comprehensive review of the physics that underlies MRI is beyond the scope of this article; several important principles are relevant to clinicians, however. Image contrast is dependent on intrinsic properties of tissue with regard to proton density, longitudinal relaxation time (T1), and transverse relaxation time (T2). Pulse sequences, which describe the strength and timing of the radiofrequency pulse and gradient pulses, define imaging acquisition parameters (eg, repetition time between the radio frequency pulse and echo time).

In turn, the intensity of the signal that is “seen” with various pulse sequences is differentially affected by intrinsic properties of tissue. At most pediatric institutions, the standard MRI-examination protocol includes: a T1-weighted image (Figure 1A); a T2-weighted scan (Figure 1B); fluid attenuated inversion recovery (FLAIR) (Figure 1C); and diffusion-weighted imaging (DWI) (Figure 1D).

Specific MRI sequences

T1 images. T1 sequences, or so-called anatomy sequences, are ideally suited for detailed neuroanatomic evaluations. They are generated in such a way that structures containing fluid are dark (hypo-intense), whereas other structures, with higher fat or protein content, are brighter (iso-intense, even hyper-intense). For this reason, CSF in the intracranial ventricles is dark, and white matter is brighter than the cortex because of lipid in myelin sheaths.

In addition, to view structural abnormalities that are characterized by altered vascular supply or flow, such as tumors and infections (abscesses), contrast imaging can be particularly helpful; such images generally are obtained as T1 sequences.

T2 images. By contrast to the T1-weighted sequence, the T2-weighted sequences emphasize fluid signal; structures such as the ventricles, which contain CSF, therefore will be bright (hyper-intense). Pathology that produces edema or fluid, such as edema surrounding demyelinating lesions or infections, also will show bright hyper-intense signal. In T2-weighted images of the brain, white matter shows lower signal intensity than the cortex because of the relatively lower water content in white matter tracts and myelin sheaths.

Fluid attenuation inversion recovery. FLAIR images are generated so that the baseline bright T2 signal seen in normal structures, such as the CSF, containing ventricles is cancelled out, or attenuated. In effect, this subtraction of typical background hyper-intense fluid signal leaves only abnormal T2 bright hyper-intense signal, such as vasogenic edema surrounding tumors, cytotoxic edema within an infarction, or extra-axial fluid collections such as a subarachnoid or subdural hemorrhage.

Diffusion-weighted imaging. DWI utilizes the random motion (ie, diffusion) of water molecules to generate contrast. In this regard, the diffusion of any molecule is influenced by its interaction with other molecules (eg, white-matter fibers and membranes, and macromolecules). Diffusion patterns therefore reflect details about tissue boundaries; as such, DWI is sensitive to a number of neurologic processes, such as ischemia, demyelinating disease, and some tumors, which restrict the free motion of water. DWI detects this so-called restricted diffusion and displays an area of bright signal.

Susceptibility-weighted imaging (SWI). In the pediatric population, SWI (Figure 2) utilizes a long-echo, 3-dimensional, velocity-compensated gradient recalled echo for image acquisition² and, ultimately, leverages susceptibility differences across tissues by employing the phase image to identify these differences. SWI, which uses both magnitude and phase images and is remarkably sensitive to venous blood (and blood products), iron, and calcifications, therefore might be of increasing utility in pediatric patients with traumatic brain injury (TBI) (Figure 2B). As such, SWI has become a critical component of many pediatric MRI studies.³

• vessel pathology and injury underlying stroke, such as vessel occlusion or injury
• patterns of vessel involvement suggestive of vasculitis
• developmental or acquired structural vascular abnormalities, such as aneurysm or vascular malformations
• determination of tumor blood supply.

MRA can be performed without or with contrast, although MRA with contrast might provide a higher quality study and therefore be of greater utility. Of note: The spatial resolution of MRA is not as good as CT angiography; abnormalities, such as a small aneurysm, might not be apparent.

Magnetic resonance venography (MRV) (Figure 3B) is most commonly performed when the possibility of thrombosis of the dural venous sinuses is being considered; it also is employed to evaluate vascular malformations, tumor drainage patterns, and other pathologic states. As with MRA, MRV can be performed without or with contrast, although post-contrast MRV is generally of higher quality and might be preferred when assessing for sinus thrombosis.

Magnetic resonance spectroscopy (MRS) resides at the border between research and clinical practice. In children and adolescents, MRS provides data on neuronal and axonal viability as well as energetics and cell membranes.⁴ Pediatric neurologists often use MRS to evaluate for congenital neurometabolic disease; this modality also can help distinguish between an active intracranial tumor from an abscess or gliosis.⁵

Neuroimaging in pediatric neuropsychiatric conditions: Evidence, guidance

Delirium (altered mental status). The acute neuropsychiatric syndrome characterized by impaired attention and sensorium might have a broad underlying etiology, but it is always associated with alteration of CNS neurophysiology. Children with neurostructural abnormalities might have increased vulnerability to CNS insult and therefore be at increased risk of delirium.⁶ Additionally, delirium can present subtly in children, with the precise signs dependent on the individual patient’s developmental stage.

Neuroimaging may be helpful when an infectious, inflammatory, toxic, or a metabolic basis for delirium is suspected, or when a patient has new focal neurologic findings. In this regard, focal neurologic findings suggest an underlying localizable lesion and warrant dedicated neuroimaging to localize the lesion.

In general, the differential diagnosis should guide consideration of neuroimaging. When considering the possibility of an unwitnessed seizure in a child who presents with altered mental status, neuroimaging certainly is an important component of the workup.

As another example, when underlying trauma, intracranial hemorrhage, or mass is a possibility in acute delirium, urgent head CT is appropriate. In non-emergent cases, MRI is the modality of choice. In immuno­compromised patients presenting with delirium, maintain a low threshold for neuroimaging with contrast to rule out opportunistic intracranial infection.

Last, in children who have hydrocephalus with a shunt, delirium could be a harbinger of underlying shunt malfunction, warranting a “shunt series.”

ADHD. The diagnosis of ADHD remains a clinical one; for the typical pediatric patient with ADHD but who does not have focal neurologic deficits, neuroimaging is unnecessary. Some structural MRI studies of youth with ADHD suggest diminished volume of the globus pallidus, putamen, and caudate⁷; other studies reveal changes in gyrification and cortical thickness⁸ in regions subserving attentional processes. However, intra-individual and developmental-related variability preclude routine use of neuroimaging in the standard diagnostic work-up of ADHD.

Nevertheless, neuroimaging should be strongly considered in a child with progressive worsening of inattention, especially if combined with other psychiatric or neurologic findings. In such a case, MRI should be obtained to evaluate for a progressive neurodegenerative leukoencephalopathy (eg, adrenoleukodystrophy).⁹

Depressive and anxiety disorders. In pediatric patients who exhibit depressive or anxiety symptoms, abnormalities have been observed in cortical thickness¹⁰ and gray matter volume,^11,12 and functional signatures¹³ have been identified in the circuitry of the prefrontal amygdala. No data suggest that, in an individual patient, neuroimaging can be of diagnostic utility—particularly in the absence of focal neurologic findings.

That being said, headache and other somatic symptoms are common in pediatric patients with a mood or anxiety disorder. Evidence for neuroimaging in the context of pediatric headache suggests that MRI should be considered when headache is associated with neurologic signs or symptoms, such as aura, or accompanied by focal neurologic deficit.¹⁴

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS). Neuroimaging studies of patients with confirmed PANDAS or PANS are rare, but group analyses suggest a decreased average volume of the caudate, putamen, and globus pallidus in patients with PANDAS compared with healthy comparison subjects, although total cerebral volume does not appear to differ.¹⁵ Moreover, thalamic findings in patients with PANDAS have been noted to be similar to what is seen in patients with Sydenham’s chorea.

The most recent consensus statement regarding the treatment and assessment of PANDAS and PANS recommends ordering brain MRI when other conditions are suspected (eg, CNS, small vessel vasculitis, limbic encephalitis) or when the patient has severe headache, gait disturbance, cognitive deterioration, or psychosis.¹⁶ Furthermore, the consensus statement notes the potential utility of T2-weighted imaging with contrast to evaluate inflammatory changes in the basal ganglia.¹⁶

Autism spectrum disorder. Significant progress has been made during the past decade on the neuroanatomic characterization of ASD. Accumulating data indicate that, in pediatric patients with ASD, (1) development of white matter and gray matter is disrupted early in the course of the disorder and (2) cortical thickness is increased in regions subserving social cognition.^17,18

Several studies have examined the presence of patient-level findings in samples of pediatric patients with ASD. Approximately 8% of pediatric patients with ASD were found to have some abnormality on routine brain MRI, the most common being white-matter signal abnormalities, dilated Virchow-Robin space, and temporal lobe abnormalities.¹⁹

Although abnormalities might be present in a large percentage of individual scans, routine screening MRI is unlikely to be of clinical utility in youth with ASD. In fact, no recommendation for routine MRI screening in patients with ASD has been made by the American Academy of Child & Adolescent Psychiatry, the Child Neurology Society of the American Academy of Neurology, or the American Academy of Pediatrics.

However, in patients with an underlying neurostructural disease that is phenotypically associated with ASD-like symptoms, imaging might be of use. In tuberous sclerosis, for example, MRI is especially important to classify intracranial lesions; determine burden and location; or identify treatment options (Figure 4). For patients with tuberous sclerosis—of whom more than one-third meet diagnostic criteria for ASD²⁰—MRI study should include FLAIR, spin-echo, and gradient-echo sequences.

Movement disorders. Hyperkinetic movement disorders, including tic disorders and drug-induced movement disorders (eg, tremor) are common in pediatric patients. In pediatric patients with a tic disorder or Tourette’s disorder (TD), neuroimaging typically is unnecessary, despite the suggestion that the caudate nucleus volume is reduced in groups of patients with TD.

Many CNS-acting medications can exacerbate physiologic tremor; in pediatric patients with symptoms of a movement disorder, home medications should be carefully reviewed for potentially offending agents. When the patient is clinically and biochemically euthyroid and medication-induced movement disorder has been ruled out, or when the patient meets clinical diagnostic criteria for TD or a tic disorder, routine neuroimaging generally is unnecessary.

When tremor accompanies other cerebellar signs, such as ataxia or dysmetria, strongly consider MRI of the brain to evaluate pathology in the posterior fossa. In addition, neuroimaging should be considered for children with a new-onset abnormality on neurologic exam, including rapid onset of abnormal movements (other than common tics), continuous progressive worsening of symptoms, or any loss of developmental milestones.

Last, although tics and stereotypies often are transient and wane with age, other abnormal movements, such as dystonia, chorea, and parkinsonism (aside from those potentially associated with antipsychotic use), are never expected during typical development and warrant MRI.

Traumatic brain injury. Prompt evaluation and intervention for TBI can significantly affect overall outcome. Moreover, there has been increased enthusiasm around the pre-hospital assessment of TBI severity using (1) any of several proprietary testing systems (eg, Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) plus (2) standard clinical staging, which is based on duration of loss of consciousness, persistence of memory loss, and the Glasgow Coma Scale score.

The goal for any TBI patient during the acute post-injury phase is to minimize continued neuronal injury from secondary effects of TBI, such as cerebral edema and herniation, and to optimize protection of surviving brain tissue; neuroimaging is a critical component of assessment during both acute and chronic recovery periods of TBI.²¹

The optimal imaging modality varies with the amount of time that has passed since initial injury.²² Urgent neuroimaging (the first 24 hours after brain injury) is typically obtained using head CT to assist decision-making in acute neurosurgical management. In this setting, head CT is fast and efficient; minimizes the amount of time that the patient is in the scanner; and provides valuable information on the acuity and extent of injury, degree of cerebral edema, and evidence or risk of pending herniation.

On the other hand, MRI is superior to CT during 48 to 72 hours after injury, given its higher resolution; superior imaging of the brainstem and deep gray nuclei; and ability to detect axonal injury, small contusions, and subtle neuronal damage. Specifically, SWI sequences can be particularly helpful in TBI for detecting diffuse axonal injury and micro-hemorrhages; several recent studies also suggest that SWI may be of particular value in pediatric patients with TBI.²³

Additionally, given the increased sensitivity of MRI to detect subtle injuries, this modality can assist in identifying chronic sequelae of brain injury—thus contributing to determining of chronic therapy options and assisting with long-term prognosis. Gross structural changes resulting from TBI often are evident even in the acute post-injury phase; synaptic remodeling continues, however, for an indefinite period after injury, and this remodeling capacity is even more pronounced in the highly plastic brain of a young child.

Microstructural changes might not be detectable using traditional, readily available imaging sequences (CT, MRI). When those traditional modalities are used in concert with functional imaging techniques (eg, PET to evaluate cerebral metabolism and SPECT imaging which can detect abnormalities in cerebral blood flow), the combination of older and newer might provide a more complete picture of recovery after TBI.²⁴

The important role of neuroimaging in severe TBI is intuitive. However, it is important to consider the role of neuroimaging in mild TBI in children, especially in the setting of repetitive mild injury.²⁵ A growing body of evidence supports close, serial monitoring of children after even mild closed head injury for neurologic and psychiatric sequelae. Although it is rare that a child who is awake, interactive, and lacking focal neurologic deficits would need emergent (ie, CT) imaging after mild closed head injury, there might be a role for MRI later in the course of that child’s recovery—especially if recovery is complicated by clinical sequelae of mild TBI, such as cognitive impairment, headaches, or altered behavior.

When is additional neuroimaging needed?

It’s worthwhile briefly reviewing 4 scenarios that you might encounter, when you work with children and adolescents, in which urgent or emergent neuroimaging (often with consultation) should be obtained. The Table describes these situations and appropriate first- and second-line interventions.

1. When the presentation of your patient is consistent with an acute neurologic deficit, acute TBI, progressive neuropsychiatric decline, CNS infection, mass, demyelinating process, or toxic exposure, neuroimaging is likely critical.

2. In patients with progressive neurologic decline, including loss of developmental milestones, MRI, MRS, and referral to neurology should be part of the comprehensive evaluation.

3. In young children who exhibit a decrease in head circumference on growth curves, MRI is important to evaluate for underlying structural causes.

4. Pediatric patients with symptoms consistent with either stroke (ie, a new, persistent neurologic deficit) or a demyelinating process (eg, multiple episodes of variable transient focal neurologic symptoms), MRI should be obtained without compunction.  

Consultation with pediatric neuroradiology

In deciding whether to obtain neuroimaging for a particular case, you should discuss your concerns with the pediatric radiologist or pediatric neuroradiologist, who will likely provide important guidance on key aspects of the study (eg, modifying slice thickness in a particular scan; recommending the use of contrast; including MRS in the order for imaging; performing appropriate vessel imaging). Consider asking 1 or more important questions when you discuss a patient’s presentation with the pediatric radiologist or pediatric neuroradiologist:

• “What neuroimaging studies are appropriate, based on my differential diagnosis?”
• “Are there specific imaging sequences that we should consider?”
• “Are there contraindications to the imaging modality for my patient?”
• “Is my patient likely to have difficulty tolerating the imaging procedure?”
• “Does my patient need sedation to tolerate this procedure?”
• “Should additional regions be included in the scan?” (Examples: In a child with stroke it might be important to include neck and chest vasculature and the heart. Other conditions might warrant imaging of the spinal cord.)

The first 15 years of the new millennium have seen a great increase in research on neuroimaging in children and adolescents who have a psychiatric disorder. In addition, imaging modalities continue to evolve, and are becoming increasingly accessible and informative. The literature is now replete with reports of neurostructural differences between patients and healthy subjects in a variety of common pediatric psychiatric conditions, including anxiety disorders, mood disorders, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD).

Historically, the clinical utility of neuroimaging was restricted to the identification of structural pathology. Today, accumulating data reveal novel roles for neuroimaging; these revelations are supported by studies demonstrating that treatment response for psychotherapeutic and psychopharmacotherapeutic interventions can be predicted by neuro­chemical and neurofunctional characteristics assessed by advanced imaging technologies, such as magnetic resonance spectroscopy (MRS) and functional MRI.

However, such advanced techniques are (at least at present) not ready for routine clinical use for this purpose. Instead, neuroimaging in the child and adolescent psychiatric clinic remains largely focused on ruling out neurostructural, neurologic, “nonpsychiatric” causes of our patients’ symptoms.

Understanding the role and limitations of major imaging modalities is key to guiding efficient and appropriate neuroimaging selection for pediatric patients. In this article, we describe and review:

• neuroimaging approaches for children and adolescents with psychiatric disorders
• the role of neuroimaging in (1) the differential diagnosis and workup of common psychiatric disorders and (2) urgent clinical situations
• how to determine what type of imaging to obtain.

Computed tomography

CT, which utilizes ionizing radiation, often is reserved, in the pediatric setting, for (1) emergency evaluation and (2) excluding potentially catastrophic neurologic injury resulting from:

• ischemic or hemorrhagic stroke
• herniation
• intracerebral hemorrhage
• subdural and epidural hematoma
• large intracranial mass with mass effect
• increased intracranial pressure
• acute skull fracture.

Although a CT scan is, typically, quick and has excellent sensitivity for acute bleeding and bony pathology, it exposes the patient to radiation and provides poor resolution compared with MRI.

In pediatrics, there has been practice-changing recognition of the importance of limiting lifetime radiation exposure incurred from medical procedures and imaging. As a result, most providers now agree that use of MRI in lieu of CT is appropriate in many, if not most, non-emergent situations. In an emergent situation, however, CT imaging is appropriate and should not be delayed. Moreover, in an emergent situation, you should not hesitate to use head CT in children, although timely discussion with the radiologist is recommended to review your differential diagnosis to better determine the preferred imaging modality.

Magnetic resonance imaging

Over the past several decades, MRI has been increasingly available in most pediatric health care facilities. The modality offers specific advantages for pediatric patients, including:

• better spatial resolution
• the ability to concurrently assess multiple pathologic processes
• lack of exposure to ionizing radiation.¹

A number of MRI sequences, described below, can be used to assess vascular, inflammatory, structural, and metabolic processes.

A look inside. Comprehensive review of the physics that underlies MRI is beyond the scope of this article; several important principles are relevant to clinicians, however. Image contrast is dependent on intrinsic properties of tissue with regard to proton density, longitudinal relaxation time (T1), and transverse relaxation time (T2). Pulse sequences, which describe the strength and timing of the radiofrequency pulse and gradient pulses, define imaging acquisition parameters (eg, repetition time between the radio frequency pulse and echo time).

In turn, the intensity of the signal that is “seen” with various pulse sequences is differentially affected by intrinsic properties of tissue. At most pediatric institutions, the standard MRI-examination protocol includes: a T1-weighted image (Figure 1A); a T2-weighted scan (Figure 1B); fluid attenuated inversion recovery (FLAIR) (Figure 1C); and diffusion-weighted imaging (DWI) (Figure 1D).

Specific MRI sequences

T1 images. T1 sequences, or so-called anatomy sequences, are ideally suited for detailed neuroanatomic evaluations. They are generated in such a way that structures containing fluid are dark (hypo-intense), whereas other structures, with higher fat or protein content, are brighter (iso-intense, even hyper-intense). For this reason, CSF in the intracranial ventricles is dark, and white matter is brighter than the cortex because of lipid in myelin sheaths.

In addition, to view structural abnormalities that are characterized by altered vascular supply or flow, such as tumors and infections (abscesses), contrast imaging can be particularly helpful; such images generally are obtained as T1 sequences.

T2 images. By contrast to the T1-weighted sequence, the T2-weighted sequences emphasize fluid signal; structures such as the ventricles, which contain CSF, therefore will be bright (hyper-intense). Pathology that produces edema or fluid, such as edema surrounding demyelinating lesions or infections, also will show bright hyper-intense signal. In T2-weighted images of the brain, white matter shows lower signal intensity than the cortex because of the relatively lower water content in white matter tracts and myelin sheaths.

Fluid attenuation inversion recovery. FLAIR images are generated so that the baseline bright T2 signal seen in normal structures, such as the CSF, containing ventricles is cancelled out, or attenuated. In effect, this subtraction of typical background hyper-intense fluid signal leaves only abnormal T2 bright hyper-intense signal, such as vasogenic edema surrounding tumors, cytotoxic edema within an infarction, or extra-axial fluid collections such as a subarachnoid or subdural hemorrhage.

Diffusion-weighted imaging. DWI utilizes the random motion (ie, diffusion) of water molecules to generate contrast. In this regard, the diffusion of any molecule is influenced by its interaction with other molecules (eg, white-matter fibers and membranes, and macromolecules). Diffusion patterns therefore reflect details about tissue boundaries; as such, DWI is sensitive to a number of neurologic processes, such as ischemia, demyelinating disease, and some tumors, which restrict the free motion of water. DWI detects this so-called restricted diffusion and displays an area of bright signal.

Susceptibility-weighted imaging (SWI). In the pediatric population, SWI (Figure 2) utilizes a long-echo, 3-dimensional, velocity-compensated gradient recalled echo for image acquisition² and, ultimately, leverages susceptibility differences across tissues by employing the phase image to identify these differences. SWI, which uses both magnitude and phase images and is remarkably sensitive to venous blood (and blood products), iron, and calcifications, therefore might be of increasing utility in pediatric patients with traumatic brain injury (TBI) (Figure 2B). As such, SWI has become a critical component of many pediatric MRI studies.³

• vessel pathology and injury underlying stroke, such as vessel occlusion or injury
• patterns of vessel involvement suggestive of vasculitis
• developmental or acquired structural vascular abnormalities, such as aneurysm or vascular malformations
• determination of tumor blood supply.

MRA can be performed without or with contrast, although MRA with contrast might provide a higher quality study and therefore be of greater utility. Of note: The spatial resolution of MRA is not as good as CT angiography; abnormalities, such as a small aneurysm, might not be apparent.

Magnetic resonance venography (MRV) (Figure 3B) is most commonly performed when the possibility of thrombosis of the dural venous sinuses is being considered; it also is employed to evaluate vascular malformations, tumor drainage patterns, and other pathologic states. As with MRA, MRV can be performed without or with contrast, although post-contrast MRV is generally of higher quality and might be preferred when assessing for sinus thrombosis.

Magnetic resonance spectroscopy (MRS) resides at the border between research and clinical practice. In children and adolescents, MRS provides data on neuronal and axonal viability as well as energetics and cell membranes.⁴ Pediatric neurologists often use MRS to evaluate for congenital neurometabolic disease; this modality also can help distinguish between an active intracranial tumor from an abscess or gliosis.⁵

Neuroimaging in pediatric neuropsychiatric conditions: Evidence, guidance

Delirium (altered mental status). The acute neuropsychiatric syndrome characterized by impaired attention and sensorium might have a broad underlying etiology, but it is always associated with alteration of CNS neurophysiology. Children with neurostructural abnormalities might have increased vulnerability to CNS insult and therefore be at increased risk of delirium.⁶ Additionally, delirium can present subtly in children, with the precise signs dependent on the individual patient’s developmental stage.

Neuroimaging may be helpful when an infectious, inflammatory, toxic, or a metabolic basis for delirium is suspected, or when a patient has new focal neurologic findings. In this regard, focal neurologic findings suggest an underlying localizable lesion and warrant dedicated neuroimaging to localize the lesion.

In general, the differential diagnosis should guide consideration of neuroimaging. When considering the possibility of an unwitnessed seizure in a child who presents with altered mental status, neuroimaging certainly is an important component of the workup.

As another example, when underlying trauma, intracranial hemorrhage, or mass is a possibility in acute delirium, urgent head CT is appropriate. In non-emergent cases, MRI is the modality of choice. In immuno­compromised patients presenting with delirium, maintain a low threshold for neuroimaging with contrast to rule out opportunistic intracranial infection.

Last, in children who have hydrocephalus with a shunt, delirium could be a harbinger of underlying shunt malfunction, warranting a “shunt series.”

ADHD. The diagnosis of ADHD remains a clinical one; for the typical pediatric patient with ADHD but who does not have focal neurologic deficits, neuroimaging is unnecessary. Some structural MRI studies of youth with ADHD suggest diminished volume of the globus pallidus, putamen, and caudate⁷; other studies reveal changes in gyrification and cortical thickness⁸ in regions subserving attentional processes. However, intra-individual and developmental-related variability preclude routine use of neuroimaging in the standard diagnostic work-up of ADHD.

Nevertheless, neuroimaging should be strongly considered in a child with progressive worsening of inattention, especially if combined with other psychiatric or neurologic findings. In such a case, MRI should be obtained to evaluate for a progressive neurodegenerative leukoencephalopathy (eg, adrenoleukodystrophy).⁹

Depressive and anxiety disorders. In pediatric patients who exhibit depressive or anxiety symptoms, abnormalities have been observed in cortical thickness¹⁰ and gray matter volume,^11,12 and functional signatures¹³ have been identified in the circuitry of the prefrontal amygdala. No data suggest that, in an individual patient, neuroimaging can be of diagnostic utility—particularly in the absence of focal neurologic findings.

That being said, headache and other somatic symptoms are common in pediatric patients with a mood or anxiety disorder. Evidence for neuroimaging in the context of pediatric headache suggests that MRI should be considered when headache is associated with neurologic signs or symptoms, such as aura, or accompanied by focal neurologic deficit.¹⁴

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS). Neuroimaging studies of patients with confirmed PANDAS or PANS are rare, but group analyses suggest a decreased average volume of the caudate, putamen, and globus pallidus in patients with PANDAS compared with healthy comparison subjects, although total cerebral volume does not appear to differ.¹⁵ Moreover, thalamic findings in patients with PANDAS have been noted to be similar to what is seen in patients with Sydenham’s chorea.

The most recent consensus statement regarding the treatment and assessment of PANDAS and PANS recommends ordering brain MRI when other conditions are suspected (eg, CNS, small vessel vasculitis, limbic encephalitis) or when the patient has severe headache, gait disturbance, cognitive deterioration, or psychosis.¹⁶ Furthermore, the consensus statement notes the potential utility of T2-weighted imaging with contrast to evaluate inflammatory changes in the basal ganglia.¹⁶

Autism spectrum disorder. Significant progress has been made during the past decade on the neuroanatomic characterization of ASD. Accumulating data indicate that, in pediatric patients with ASD, (1) development of white matter and gray matter is disrupted early in the course of the disorder and (2) cortical thickness is increased in regions subserving social cognition.^17,18

Several studies have examined the presence of patient-level findings in samples of pediatric patients with ASD. Approximately 8% of pediatric patients with ASD were found to have some abnormality on routine brain MRI, the most common being white-matter signal abnormalities, dilated Virchow-Robin space, and temporal lobe abnormalities.¹⁹

Although abnormalities might be present in a large percentage of individual scans, routine screening MRI is unlikely to be of clinical utility in youth with ASD. In fact, no recommendation for routine MRI screening in patients with ASD has been made by the American Academy of Child & Adolescent Psychiatry, the Child Neurology Society of the American Academy of Neurology, or the American Academy of Pediatrics.

However, in patients with an underlying neurostructural disease that is phenotypically associated with ASD-like symptoms, imaging might be of use. In tuberous sclerosis, for example, MRI is especially important to classify intracranial lesions; determine burden and location; or identify treatment options (Figure 4). For patients with tuberous sclerosis—of whom more than one-third meet diagnostic criteria for ASD²⁰—MRI study should include FLAIR, spin-echo, and gradient-echo sequences.

Movement disorders. Hyperkinetic movement disorders, including tic disorders and drug-induced movement disorders (eg, tremor) are common in pediatric patients. In pediatric patients with a tic disorder or Tourette’s disorder (TD), neuroimaging typically is unnecessary, despite the suggestion that the caudate nucleus volume is reduced in groups of patients with TD.

Many CNS-acting medications can exacerbate physiologic tremor; in pediatric patients with symptoms of a movement disorder, home medications should be carefully reviewed for potentially offending agents. When the patient is clinically and biochemically euthyroid and medication-induced movement disorder has been ruled out, or when the patient meets clinical diagnostic criteria for TD or a tic disorder, routine neuroimaging generally is unnecessary.

When tremor accompanies other cerebellar signs, such as ataxia or dysmetria, strongly consider MRI of the brain to evaluate pathology in the posterior fossa. In addition, neuroimaging should be considered for children with a new-onset abnormality on neurologic exam, including rapid onset of abnormal movements (other than common tics), continuous progressive worsening of symptoms, or any loss of developmental milestones.

Last, although tics and stereotypies often are transient and wane with age, other abnormal movements, such as dystonia, chorea, and parkinsonism (aside from those potentially associated with antipsychotic use), are never expected during typical development and warrant MRI.

Traumatic brain injury. Prompt evaluation and intervention for TBI can significantly affect overall outcome. Moreover, there has been increased enthusiasm around the pre-hospital assessment of TBI severity using (1) any of several proprietary testing systems (eg, Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) plus (2) standard clinical staging, which is based on duration of loss of consciousness, persistence of memory loss, and the Glasgow Coma Scale score.

The goal for any TBI patient during the acute post-injury phase is to minimize continued neuronal injury from secondary effects of TBI, such as cerebral edema and herniation, and to optimize protection of surviving brain tissue; neuroimaging is a critical component of assessment during both acute and chronic recovery periods of TBI.²¹

The optimal imaging modality varies with the amount of time that has passed since initial injury.²² Urgent neuroimaging (the first 24 hours after brain injury) is typically obtained using head CT to assist decision-making in acute neurosurgical management. In this setting, head CT is fast and efficient; minimizes the amount of time that the patient is in the scanner; and provides valuable information on the acuity and extent of injury, degree of cerebral edema, and evidence or risk of pending herniation.

On the other hand, MRI is superior to CT during 48 to 72 hours after injury, given its higher resolution; superior imaging of the brainstem and deep gray nuclei; and ability to detect axonal injury, small contusions, and subtle neuronal damage. Specifically, SWI sequences can be particularly helpful in TBI for detecting diffuse axonal injury and micro-hemorrhages; several recent studies also suggest that SWI may be of particular value in pediatric patients with TBI.²³

Additionally, given the increased sensitivity of MRI to detect subtle injuries, this modality can assist in identifying chronic sequelae of brain injury—thus contributing to determining of chronic therapy options and assisting with long-term prognosis. Gross structural changes resulting from TBI often are evident even in the acute post-injury phase; synaptic remodeling continues, however, for an indefinite period after injury, and this remodeling capacity is even more pronounced in the highly plastic brain of a young child.

Microstructural changes might not be detectable using traditional, readily available imaging sequences (CT, MRI). When those traditional modalities are used in concert with functional imaging techniques (eg, PET to evaluate cerebral metabolism and SPECT imaging which can detect abnormalities in cerebral blood flow), the combination of older and newer might provide a more complete picture of recovery after TBI.²⁴

The important role of neuroimaging in severe TBI is intuitive. However, it is important to consider the role of neuroimaging in mild TBI in children, especially in the setting of repetitive mild injury.²⁵ A growing body of evidence supports close, serial monitoring of children after even mild closed head injury for neurologic and psychiatric sequelae. Although it is rare that a child who is awake, interactive, and lacking focal neurologic deficits would need emergent (ie, CT) imaging after mild closed head injury, there might be a role for MRI later in the course of that child’s recovery—especially if recovery is complicated by clinical sequelae of mild TBI, such as cognitive impairment, headaches, or altered behavior.

When is additional neuroimaging needed?

It’s worthwhile briefly reviewing 4 scenarios that you might encounter, when you work with children and adolescents, in which urgent or emergent neuroimaging (often with consultation) should be obtained. The Table describes these situations and appropriate first- and second-line interventions.

1. When the presentation of your patient is consistent with an acute neurologic deficit, acute TBI, progressive neuropsychiatric decline, CNS infection, mass, demyelinating process, or toxic exposure, neuroimaging is likely critical.

2. In patients with progressive neurologic decline, including loss of developmental milestones, MRI, MRS, and referral to neurology should be part of the comprehensive evaluation.

3. In young children who exhibit a decrease in head circumference on growth curves, MRI is important to evaluate for underlying structural causes.

4. Pediatric patients with symptoms consistent with either stroke (ie, a new, persistent neurologic deficit) or a demyelinating process (eg, multiple episodes of variable transient focal neurologic symptoms), MRI should be obtained without compunction.  

Consultation with pediatric neuroradiology

In deciding whether to obtain neuroimaging for a particular case, you should discuss your concerns with the pediatric radiologist or pediatric neuroradiologist, who will likely provide important guidance on key aspects of the study (eg, modifying slice thickness in a particular scan; recommending the use of contrast; including MRS in the order for imaging; performing appropriate vessel imaging). Consider asking 1 or more important questions when you discuss a patient’s presentation with the pediatric radiologist or pediatric neuroradiologist:

• “What neuroimaging studies are appropriate, based on my differential diagnosis?”
• “Are there specific imaging sequences that we should consider?”
• “Are there contraindications to the imaging modality for my patient?”
• “Is my patient likely to have difficulty tolerating the imaging procedure?”
• “Does my patient need sedation to tolerate this procedure?”
• “Should additional regions be included in the scan?” (Examples: In a child with stroke it might be important to include neck and chest vasculature and the heart. Other conditions might warrant imaging of the spinal cord.)

The first 15 years of the new millennium have seen a great increase in research on neuroimaging in children and adolescents who have a psychiatric disorder. In addition, imaging modalities continue to evolve, and are becoming increasingly accessible and informative. The literature is now replete with reports of neurostructural differences between patients and healthy subjects in a variety of common pediatric psychiatric conditions, including anxiety disorders, mood disorders, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD).

Historically, the clinical utility of neuroimaging was restricted to the identification of structural pathology. Today, accumulating data reveal novel roles for neuroimaging; these revelations are supported by studies demonstrating that treatment response for psychotherapeutic and psychopharmacotherapeutic interventions can be predicted by neuro­chemical and neurofunctional characteristics assessed by advanced imaging technologies, such as magnetic resonance spectroscopy (MRS) and functional MRI.

However, such advanced techniques are (at least at present) not ready for routine clinical use for this purpose. Instead, neuroimaging in the child and adolescent psychiatric clinic remains largely focused on ruling out neurostructural, neurologic, “nonpsychiatric” causes of our patients’ symptoms.

Understanding the role and limitations of major imaging modalities is key to guiding efficient and appropriate neuroimaging selection for pediatric patients. In this article, we describe and review:

• neuroimaging approaches for children and adolescents with psychiatric disorders
• the role of neuroimaging in (1) the differential diagnosis and workup of common psychiatric disorders and (2) urgent clinical situations
• how to determine what type of imaging to obtain.

Computed tomography

CT, which utilizes ionizing radiation, often is reserved, in the pediatric setting, for (1) emergency evaluation and (2) excluding potentially catastrophic neurologic injury resulting from:

• ischemic or hemorrhagic stroke
• herniation
• intracerebral hemorrhage
• subdural and epidural hematoma
• large intracranial mass with mass effect
• increased intracranial pressure
• acute skull fracture.

Although a CT scan is, typically, quick and has excellent sensitivity for acute bleeding and bony pathology, it exposes the patient to radiation and provides poor resolution compared with MRI.

In pediatrics, there has been practice-changing recognition of the importance of limiting lifetime radiation exposure incurred from medical procedures and imaging. As a result, most providers now agree that use of MRI in lieu of CT is appropriate in many, if not most, non-emergent situations. In an emergent situation, however, CT imaging is appropriate and should not be delayed. Moreover, in an emergent situation, you should not hesitate to use head CT in children, although timely discussion with the radiologist is recommended to review your differential diagnosis to better determine the preferred imaging modality.

Magnetic resonance imaging

Over the past several decades, MRI has been increasingly available in most pediatric health care facilities. The modality offers specific advantages for pediatric patients, including:

• better spatial resolution
• the ability to concurrently assess multiple pathologic processes
• lack of exposure to ionizing radiation.¹

A number of MRI sequences, described below, can be used to assess vascular, inflammatory, structural, and metabolic processes.

A look inside. Comprehensive review of the physics that underlies MRI is beyond the scope of this article; several important principles are relevant to clinicians, however. Image contrast is dependent on intrinsic properties of tissue with regard to proton density, longitudinal relaxation time (T1), and transverse relaxation time (T2). Pulse sequences, which describe the strength and timing of the radiofrequency pulse and gradient pulses, define imaging acquisition parameters (eg, repetition time between the radio frequency pulse and echo time).

In turn, the intensity of the signal that is “seen” with various pulse sequences is differentially affected by intrinsic properties of tissue. At most pediatric institutions, the standard MRI-examination protocol includes: a T1-weighted image (Figure 1A); a T2-weighted scan (Figure 1B); fluid attenuated inversion recovery (FLAIR) (Figure 1C); and diffusion-weighted imaging (DWI) (Figure 1D).

Specific MRI sequences

T1 images. T1 sequences, or so-called anatomy sequences, are ideally suited for detailed neuroanatomic evaluations. They are generated in such a way that structures containing fluid are dark (hypo-intense), whereas other structures, with higher fat or protein content, are brighter (iso-intense, even hyper-intense). For this reason, CSF in the intracranial ventricles is dark, and white matter is brighter than the cortex because of lipid in myelin sheaths.

In addition, to view structural abnormalities that are characterized by altered vascular supply or flow, such as tumors and infections (abscesses), contrast imaging can be particularly helpful; such images generally are obtained as T1 sequences.

T2 images. By contrast to the T1-weighted sequence, the T2-weighted sequences emphasize fluid signal; structures such as the ventricles, which contain CSF, therefore will be bright (hyper-intense). Pathology that produces edema or fluid, such as edema surrounding demyelinating lesions or infections, also will show bright hyper-intense signal. In T2-weighted images of the brain, white matter shows lower signal intensity than the cortex because of the relatively lower water content in white matter tracts and myelin sheaths.

Fluid attenuation inversion recovery. FLAIR images are generated so that the baseline bright T2 signal seen in normal structures, such as the CSF, containing ventricles is cancelled out, or attenuated. In effect, this subtraction of typical background hyper-intense fluid signal leaves only abnormal T2 bright hyper-intense signal, such as vasogenic edema surrounding tumors, cytotoxic edema within an infarction, or extra-axial fluid collections such as a subarachnoid or subdural hemorrhage.

Diffusion-weighted imaging. DWI utilizes the random motion (ie, diffusion) of water molecules to generate contrast. In this regard, the diffusion of any molecule is influenced by its interaction with other molecules (eg, white-matter fibers and membranes, and macromolecules). Diffusion patterns therefore reflect details about tissue boundaries; as such, DWI is sensitive to a number of neurologic processes, such as ischemia, demyelinating disease, and some tumors, which restrict the free motion of water. DWI detects this so-called restricted diffusion and displays an area of bright signal.

Susceptibility-weighted imaging (SWI). In the pediatric population, SWI (Figure 2) utilizes a long-echo, 3-dimensional, velocity-compensated gradient recalled echo for image acquisition² and, ultimately, leverages susceptibility differences across tissues by employing the phase image to identify these differences. SWI, which uses both magnitude and phase images and is remarkably sensitive to venous blood (and blood products), iron, and calcifications, therefore might be of increasing utility in pediatric patients with traumatic brain injury (TBI) (Figure 2B). As such, SWI has become a critical component of many pediatric MRI studies.³

• vessel pathology and injury underlying stroke, such as vessel occlusion or injury
• patterns of vessel involvement suggestive of vasculitis
• developmental or acquired structural vascular abnormalities, such as aneurysm or vascular malformations
• determination of tumor blood supply.

MRA can be performed without or with contrast, although MRA with contrast might provide a higher quality study and therefore be of greater utility. Of note: The spatial resolution of MRA is not as good as CT angiography; abnormalities, such as a small aneurysm, might not be apparent.

Magnetic resonance venography (MRV) (Figure 3B) is most commonly performed when the possibility of thrombosis of the dural venous sinuses is being considered; it also is employed to evaluate vascular malformations, tumor drainage patterns, and other pathologic states. As with MRA, MRV can be performed without or with contrast, although post-contrast MRV is generally of higher quality and might be preferred when assessing for sinus thrombosis.

Magnetic resonance spectroscopy (MRS) resides at the border between research and clinical practice. In children and adolescents, MRS provides data on neuronal and axonal viability as well as energetics and cell membranes.⁴ Pediatric neurologists often use MRS to evaluate for congenital neurometabolic disease; this modality also can help distinguish between an active intracranial tumor from an abscess or gliosis.⁵

Neuroimaging in pediatric neuropsychiatric conditions: Evidence, guidance

Delirium (altered mental status). The acute neuropsychiatric syndrome characterized by impaired attention and sensorium might have a broad underlying etiology, but it is always associated with alteration of CNS neurophysiology. Children with neurostructural abnormalities might have increased vulnerability to CNS insult and therefore be at increased risk of delirium.⁶ Additionally, delirium can present subtly in children, with the precise signs dependent on the individual patient’s developmental stage.

Neuroimaging may be helpful when an infectious, inflammatory, toxic, or a metabolic basis for delirium is suspected, or when a patient has new focal neurologic findings. In this regard, focal neurologic findings suggest an underlying localizable lesion and warrant dedicated neuroimaging to localize the lesion.

In general, the differential diagnosis should guide consideration of neuroimaging. When considering the possibility of an unwitnessed seizure in a child who presents with altered mental status, neuroimaging certainly is an important component of the workup.

As another example, when underlying trauma, intracranial hemorrhage, or mass is a possibility in acute delirium, urgent head CT is appropriate. In non-emergent cases, MRI is the modality of choice. In immuno­compromised patients presenting with delirium, maintain a low threshold for neuroimaging with contrast to rule out opportunistic intracranial infection.

Last, in children who have hydrocephalus with a shunt, delirium could be a harbinger of underlying shunt malfunction, warranting a “shunt series.”

ADHD. The diagnosis of ADHD remains a clinical one; for the typical pediatric patient with ADHD but who does not have focal neurologic deficits, neuroimaging is unnecessary. Some structural MRI studies of youth with ADHD suggest diminished volume of the globus pallidus, putamen, and caudate⁷; other studies reveal changes in gyrification and cortical thickness⁸ in regions subserving attentional processes. However, intra-individual and developmental-related variability preclude routine use of neuroimaging in the standard diagnostic work-up of ADHD.

Nevertheless, neuroimaging should be strongly considered in a child with progressive worsening of inattention, especially if combined with other psychiatric or neurologic findings. In such a case, MRI should be obtained to evaluate for a progressive neurodegenerative leukoencephalopathy (eg, adrenoleukodystrophy).⁹

Depressive and anxiety disorders. In pediatric patients who exhibit depressive or anxiety symptoms, abnormalities have been observed in cortical thickness¹⁰ and gray matter volume,^11,12 and functional signatures¹³ have been identified in the circuitry of the prefrontal amygdala. No data suggest that, in an individual patient, neuroimaging can be of diagnostic utility—particularly in the absence of focal neurologic findings.

That being said, headache and other somatic symptoms are common in pediatric patients with a mood or anxiety disorder. Evidence for neuroimaging in the context of pediatric headache suggests that MRI should be considered when headache is associated with neurologic signs or symptoms, such as aura, or accompanied by focal neurologic deficit.¹⁴

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS). Neuroimaging studies of patients with confirmed PANDAS or PANS are rare, but group analyses suggest a decreased average volume of the caudate, putamen, and globus pallidus in patients with PANDAS compared with healthy comparison subjects, although total cerebral volume does not appear to differ.¹⁵ Moreover, thalamic findings in patients with PANDAS have been noted to be similar to what is seen in patients with Sydenham’s chorea.

The most recent consensus statement regarding the treatment and assessment of PANDAS and PANS recommends ordering brain MRI when other conditions are suspected (eg, CNS, small vessel vasculitis, limbic encephalitis) or when the patient has severe headache, gait disturbance, cognitive deterioration, or psychosis.¹⁶ Furthermore, the consensus statement notes the potential utility of T2-weighted imaging with contrast to evaluate inflammatory changes in the basal ganglia.¹⁶

Autism spectrum disorder. Significant progress has been made during the past decade on the neuroanatomic characterization of ASD. Accumulating data indicate that, in pediatric patients with ASD, (1) development of white matter and gray matter is disrupted early in the course of the disorder and (2) cortical thickness is increased in regions subserving social cognition.^17,18

Several studies have examined the presence of patient-level findings in samples of pediatric patients with ASD. Approximately 8% of pediatric patients with ASD were found to have some abnormality on routine brain MRI, the most common being white-matter signal abnormalities, dilated Virchow-Robin space, and temporal lobe abnormalities.¹⁹

Although abnormalities might be present in a large percentage of individual scans, routine screening MRI is unlikely to be of clinical utility in youth with ASD. In fact, no recommendation for routine MRI screening in patients with ASD has been made by the American Academy of Child & Adolescent Psychiatry, the Child Neurology Society of the American Academy of Neurology, or the American Academy of Pediatrics.

However, in patients with an underlying neurostructural disease that is phenotypically associated with ASD-like symptoms, imaging might be of use. In tuberous sclerosis, for example, MRI is especially important to classify intracranial lesions; determine burden and location; or identify treatment options (Figure 4). For patients with tuberous sclerosis—of whom more than one-third meet diagnostic criteria for ASD²⁰—MRI study should include FLAIR, spin-echo, and gradient-echo sequences.

Movement disorders. Hyperkinetic movement disorders, including tic disorders and drug-induced movement disorders (eg, tremor) are common in pediatric patients. In pediatric patients with a tic disorder or Tourette’s disorder (TD), neuroimaging typically is unnecessary, despite the suggestion that the caudate nucleus volume is reduced in groups of patients with TD.

Many CNS-acting medications can exacerbate physiologic tremor; in pediatric patients with symptoms of a movement disorder, home medications should be carefully reviewed for potentially offending agents. When the patient is clinically and biochemically euthyroid and medication-induced movement disorder has been ruled out, or when the patient meets clinical diagnostic criteria for TD or a tic disorder, routine neuroimaging generally is unnecessary.

When tremor accompanies other cerebellar signs, such as ataxia or dysmetria, strongly consider MRI of the brain to evaluate pathology in the posterior fossa. In addition, neuroimaging should be considered for children with a new-onset abnormality on neurologic exam, including rapid onset of abnormal movements (other than common tics), continuous progressive worsening of symptoms, or any loss of developmental milestones.

Last, although tics and stereotypies often are transient and wane with age, other abnormal movements, such as dystonia, chorea, and parkinsonism (aside from those potentially associated with antipsychotic use), are never expected during typical development and warrant MRI.

Traumatic brain injury. Prompt evaluation and intervention for TBI can significantly affect overall outcome. Moreover, there has been increased enthusiasm around the pre-hospital assessment of TBI severity using (1) any of several proprietary testing systems (eg, Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) plus (2) standard clinical staging, which is based on duration of loss of consciousness, persistence of memory loss, and the Glasgow Coma Scale score.

The goal for any TBI patient during the acute post-injury phase is to minimize continued neuronal injury from secondary effects of TBI, such as cerebral edema and herniation, and to optimize protection of surviving brain tissue; neuroimaging is a critical component of assessment during both acute and chronic recovery periods of TBI.²¹

The optimal imaging modality varies with the amount of time that has passed since initial injury.²² Urgent neuroimaging (the first 24 hours after brain injury) is typically obtained using head CT to assist decision-making in acute neurosurgical management. In this setting, head CT is fast and efficient; minimizes the amount of time that the patient is in the scanner; and provides valuable information on the acuity and extent of injury, degree of cerebral edema, and evidence or risk of pending herniation.

On the other hand, MRI is superior to CT during 48 to 72 hours after injury, given its higher resolution; superior imaging of the brainstem and deep gray nuclei; and ability to detect axonal injury, small contusions, and subtle neuronal damage. Specifically, SWI sequences can be particularly helpful in TBI for detecting diffuse axonal injury and micro-hemorrhages; several recent studies also suggest that SWI may be of particular value in pediatric patients with TBI.²³

Additionally, given the increased sensitivity of MRI to detect subtle injuries, this modality can assist in identifying chronic sequelae of brain injury—thus contributing to determining of chronic therapy options and assisting with long-term prognosis. Gross structural changes resulting from TBI often are evident even in the acute post-injury phase; synaptic remodeling continues, however, for an indefinite period after injury, and this remodeling capacity is even more pronounced in the highly plastic brain of a young child.

Microstructural changes might not be detectable using traditional, readily available imaging sequences (CT, MRI). When those traditional modalities are used in concert with functional imaging techniques (eg, PET to evaluate cerebral metabolism and SPECT imaging which can detect abnormalities in cerebral blood flow), the combination of older and newer might provide a more complete picture of recovery after TBI.²⁴

The important role of neuroimaging in severe TBI is intuitive. However, it is important to consider the role of neuroimaging in mild TBI in children, especially in the setting of repetitive mild injury.²⁵ A growing body of evidence supports close, serial monitoring of children after even mild closed head injury for neurologic and psychiatric sequelae. Although it is rare that a child who is awake, interactive, and lacking focal neurologic deficits would need emergent (ie, CT) imaging after mild closed head injury, there might be a role for MRI later in the course of that child’s recovery—especially if recovery is complicated by clinical sequelae of mild TBI, such as cognitive impairment, headaches, or altered behavior.

When is additional neuroimaging needed?

It’s worthwhile briefly reviewing 4 scenarios that you might encounter, when you work with children and adolescents, in which urgent or emergent neuroimaging (often with consultation) should be obtained. The Table describes these situations and appropriate first- and second-line interventions.

1. When the presentation of your patient is consistent with an acute neurologic deficit, acute TBI, progressive neuropsychiatric decline, CNS infection, mass, demyelinating process, or toxic exposure, neuroimaging is likely critical.

2. In patients with progressive neurologic decline, including loss of developmental milestones, MRI, MRS, and referral to neurology should be part of the comprehensive evaluation.

3. In young children who exhibit a decrease in head circumference on growth curves, MRI is important to evaluate for underlying structural causes.

4. Pediatric patients with symptoms consistent with either stroke (ie, a new, persistent neurologic deficit) or a demyelinating process (eg, multiple episodes of variable transient focal neurologic symptoms), MRI should be obtained without compunction.  

Consultation with pediatric neuroradiology

In deciding whether to obtain neuroimaging for a particular case, you should discuss your concerns with the pediatric radiologist or pediatric neuroradiologist, who will likely provide important guidance on key aspects of the study (eg, modifying slice thickness in a particular scan; recommending the use of contrast; including MRS in the order for imaging; performing appropriate vessel imaging). Consider asking 1 or more important questions when you discuss a patient’s presentation with the pediatric radiologist or pediatric neuroradiologist:

• “What neuroimaging studies are appropriate, based on my differential diagnosis?”
• “Are there specific imaging sequences that we should consider?”
• “Are there contraindications to the imaging modality for my patient?”
• “Is my patient likely to have difficulty tolerating the imaging procedure?”
• “Does my patient need sedation to tolerate this procedure?”
• “Should additional regions be included in the scan?” (Examples: In a child with stroke it might be important to include neck and chest vasculature and the heart. Other conditions might warrant imaging of the spinal cord.)

Pseudobulbar affect (PBA) is a disorder of affective expression that manifests as stereotyped and frequent outbursts of crying (not limited to lacrimation) or laughter. Symptoms are involuntary, uncontrolled, and exaggerated or incongruent with current mood. Episodes, lasting a few seconds to several minutes, may be unprovoked or occur in response to a mild stimulus, and patients typically display a normal affect between episodes.¹ PBA is estimated to affect 1 to 2 million people in the United States, although some studies suggest as many as 7 million,^1,2 depending on the evaluation method and threshold criteria used.³

 Where to look for pseudobulbar affect

 PBA has been most commonly described in 6 major  neurologic disorders:

• Alzheimer’s disease
• amyotrophic lateral sclerosis (ALS)
• multiple sclerosis (MS)
• Parkinson’s disease
• stroke
• traumatic brain injury (TBI).

Of these disorders, most studies have found the highest PBA prevalence in patients with ALS and TBI, with lesser (although significant) prevalence in Parkinson’s disease (Table 2).^1,12 These “big 6” diagnoses are not a comprehensive list, as many other disease states are associated with PBA (Table 3).^12-14

2 Pathways: ‘Generator’ and ‘governor’

Despite the many and varied injuries and illnesses associated with PBA, Lauterbach et al¹⁰ noted patterns that suggest dysregulation of 2 distinct but interconnected brain pathways: an emotional pathway controlled by a separate volitional pathway. Lesions to the volitional pathway (or its associated feedback or processing circuits) are thought to cause PBA symptoms.

To borrow an analogy from engineering, the emotional pathway is the “generator” of affect, whereas the volitional pathway is the “governor” of affect. Thus, injury to the “governor” results in overspill, or overflow, of affect that usually would be suppressed.

The emotional pathway, which coordinates the motor aspect of reflex laughing or crying, originates at the frontotemporal cortex, relaying to the amygdala and hypothalamus, then projecting to the dorsal brainstem, which includes the midbrain-pontine periaqueductal gray (PAG), dorsal tegmentum, and related brainstem.

The volitional pathway, which regulates the emotional pathway, originates in the dorsal and lateral frontoparietal cortex, projects through the internal capsule and midbrain basis pedunculi, and continues on to the anteroventral basis pontis. The basis pontis then serves as an afferent relay center for cerebellar activity. Projections from the pons then regulate the emotional circuitry primarily at the level of the PAG.¹⁰

Lesions of the volitional pathway have been correlated with conditions of PBA, whereas direct activation of the emotional pathway tended to lead to emotional lability or the crying and laughing behaviors observed in dacrystic or gelastic epilepsy.¹⁰ The pivotal nature of the regulation occurring at the PAG has guided treatment options. Neurotransmitter receptors most closely associated with this region include glutamatergic N-methyl-d-aspartate (NMDA), muscarinic M1 to M3, γ-aminobutyric acid (GABA)-A, dopamine D2, norepinephrine α-1 and α-2, serotonin 5-HT1B/D, and sigma-1 receptors. Volitional inhibition of the PAG is mediated by acetylcholine and GABA balance at this location.¹⁰

When to screen for PBA

Ask the right question. PBA as a disease state likely has been widely under-reported, under-recognized, and misdiagnosed (typically, as a primary mood disorder).⁹ Three factors underscore this problem:

• Patients do not specifically report symptoms of affective disturbance (perhaps because they lack a vocabulary to separate concepts of mood and affect)
• Physicians do not ask patients about separations of mood and affect
• Perhaps most importantly, PBA lacks a general awareness and understanding.

Co-occurring mood disorders also may thwart PBA detection. One study of PBA in Alzheimer’s dementia found that 53% of patients with symptoms consistent with PBA also had a distinct mood disorder.¹⁷ This suggests that a PBA-specific screening test is needed for accurate diagnosis.

A single question might best refine the likelihood that a patient has PBA: “Do you ever cry for no reason?” In primary psychiatric illness, crying typically is associated with a specific trigger (eg, depressed mood, despair, anxiety). A patient’s inability to identify a trigger for crying suggests the pathological separation of mood and affect—the core of PBA, and worthy of further investigation.

Clinical rating scales that correlate to disease severity appear to be the most effective in identifying PBA. The PRISM study, to date the largest clinic-based study of PBA symptoms, used the Center for Neurologic Study-Liability Scale (CNS-LS) to gauge the presence and severity of PBA symptoms.¹ A 7-question, patient self-administered tool, the CNS-LS is graded on a 5-point Likert scale. A score ≥13 has high sensitivity and specificity for diagnosis of PBA, compared with physician diagnosis.

Another option, the 16-question Pathological Laughing and Crying Scale, is a clinician-administered screening tool. Again, a score ≥13 is consistent with symptoms required for a PBA diagnosis.

Treating PBA symptoms

Until recently, most pharmacotherapeutic interventions for PBA were based on off-label use of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). From 1980 to 2010, only 7 of 22 case reports or trials of TCAs or SSRIs for PBA were randomized, double-blind, and placebo-controlled. Five had 12 to 28 patients, and 2 had 106 and 128 patients, respectively. Only 1 controlled trial included a validated symptom severity scale, and none included a scale validated for PBA.¹⁸

In particular, imipramine and nortriptyline were studied for managing PBA in patients with stroke; amitriptyline, in patients with MS; and various SSRIs, in patients with stroke.¹¹ Response of PBA symptoms to antidepressant therapy was greater in all placebo-controlled trials than response to placebo.¹⁸ As seen in pharmacotherapy of depression, the lower burden of adverse effects and overall better tolerability of SSRIs resulted in their preferred use over TCAs. In some cases, the side effects of TCAs can be leveraged for therapeutic gain. If insomnia is a problem, a nighttime dose of a TCA could ameliorate this. Similarly, if a patient has sialorrhea, the anticholinergic effect of a TCA may show some benefit.¹⁹

Dextromethorphan plus quinidine. Dextromethorphan has long been of interest for a variety of neurodegenerative diseases. Studies of its efficacy were largely unsuccessful, however, because rapid metabolism by cytochrome P450 (CYP) 2D6 prevented CNS penetration.²⁰ Quinidine is an avid inhibitor of CYP2D6, even at very low dosages. Adding quinidine to dextromethorphan limits metabolism, allowing dextromethorphan to accumulate to a plasma concentration sufficient to penetrate the CNS.¹² In 2010, the combination agent dextromethorphan hydrobromide (20 mg)/quinidine (10 mg) (DM/Q) became the first treatment to receive FDA approval for managing PBA.¹¹

Mechanism of action. The exact mechanism of DM/Q in PBA remains unknown. Dextromethorphan is an agonist of sigma-1 receptors and a relatively specific noncompetitive antagonist of NMDA receptors. It also has been shown to modulate glutamate and serotonin neurotransmission and ion channel function.²⁰ Sigma-1 receptors are concentrated in the brainstem and parts of the cerebellum that are thought to coordinate motor emotional responses. Agonism of sigma-1 receptors on glutamatergic neurons has been proposed to limit release of glutamate from the presynaptic neuron while also limiting downstream transmission of glutamatergic signal in postsynaptic neurons.

Clinical trials. Two large trials have demonstrated efficacy of DM/Q in PBA. STAR was a 12-week, double-blind, placebo-controlled trial with 326 patients diagnosed with ALS or MS who showed PBA symptoms (CNS-LS score ≥13). Compared with placebo, DM/Q use was associated with significantly reduced (P < .01) daily episodes of PBA at 2, 4, 8, and 12 weeks.²⁰ The effect was rapid, with 30% fewer PBA episodes after the first week (P < .0167). At 12 weeks, 51% of patients on DM/Q had been symptom-free for at least 2 weeks.

The PRISM II study examined the efficacy of DM/Q in managing PBA in 102 individuals with dementia, 92 with stroke, and 67 with TBI. After 30 and 90 days, CNL-LS scores were significantly reduced (P < .001) compared with baseline scores.²⁰

Prescribing information. Dextro­methorphan—typically in the form of cough syrup—has been implicated as a substance of abuse. A placebo-controlled trial demonstrated that co-administering quinidine with dextromethorphan limits measures of positive reinforcement, such as euphoria and drug liking. This suggests that quinidine may be used to reduce abuse of dextromethorphan.²⁰ As such, the abuse potential of DM/Q appears to be low.

The most common adverse effects reported with DM/Q are diarrhea, dizziness, and cough.¹² Notably, patients who received DM/Q in the STAR trial were more likely to report dizziness than those receiving placebo (10.3% vs 5.5%), but patients receiving placebo were more likely to fall.^21,22

Package labeling warns that DM/Q causes dose-dependent QTc prolongation.²¹ Quinidine can be associated with significant QTc prolongation when dosed at antiarrhythmic levels, although mean plasma concentrations found with the 10 mg of quinidine in the approved DM/Q formulation are 1% to 3% of those associated with typical dosages used in antiarrhythmic therapy. Electrophysiology studies of quinidine 10 mg dosed every 12 hours have demonstrated a mean QTc increase at steady state of 6.8 milliseconds, compared with 9.1 milliseconds for a reference control (moxifloxacin).^12,21

Although this would seem to indicate a relatively low risk of clinically significant QTc prolongation at these ultra-low dosages of quinidine, it may be advisable to obtain an initial pre-dose and post-dose ECG and longitudinally monitor the QTc interval in patients with conditions that predispose to cardiac arrhythmias. Because quinidine inhibits CYP2D6, use caution when prescribing and monitoring other medications metabolized by this pathway.

Bottom Line

Pseudobulbar affect (PBA) is a disorder of affective expression that manifests as stereotyped and frequent outbursts of crying (not limited to lacrimation) or laughter. Symptoms are involuntary, uncontrolled, and exaggerated or incongruent with current mood. Episodes, lasting a few seconds to several minutes, may be unprovoked or occur in response to a mild stimulus, and patients typically display a normal affect between episodes.¹ PBA is estimated to affect 1 to 2 million people in the United States, although some studies suggest as many as 7 million,^1,2 depending on the evaluation method and threshold criteria used.³

 Where to look for pseudobulbar affect

 PBA has been most commonly described in 6 major  neurologic disorders:

• Alzheimer’s disease
• amyotrophic lateral sclerosis (ALS)
• multiple sclerosis (MS)
• Parkinson’s disease
• stroke
• traumatic brain injury (TBI).

Of these disorders, most studies have found the highest PBA prevalence in patients with ALS and TBI, with lesser (although significant) prevalence in Parkinson’s disease (Table 2).^1,12 These “big 6” diagnoses are not a comprehensive list, as many other disease states are associated with PBA (Table 3).^12-14

2 Pathways: ‘Generator’ and ‘governor’

Despite the many and varied injuries and illnesses associated with PBA, Lauterbach et al¹⁰ noted patterns that suggest dysregulation of 2 distinct but interconnected brain pathways: an emotional pathway controlled by a separate volitional pathway. Lesions to the volitional pathway (or its associated feedback or processing circuits) are thought to cause PBA symptoms.

To borrow an analogy from engineering, the emotional pathway is the “generator” of affect, whereas the volitional pathway is the “governor” of affect. Thus, injury to the “governor” results in overspill, or overflow, of affect that usually would be suppressed.

The emotional pathway, which coordinates the motor aspect of reflex laughing or crying, originates at the frontotemporal cortex, relaying to the amygdala and hypothalamus, then projecting to the dorsal brainstem, which includes the midbrain-pontine periaqueductal gray (PAG), dorsal tegmentum, and related brainstem.

The volitional pathway, which regulates the emotional pathway, originates in the dorsal and lateral frontoparietal cortex, projects through the internal capsule and midbrain basis pedunculi, and continues on to the anteroventral basis pontis. The basis pontis then serves as an afferent relay center for cerebellar activity. Projections from the pons then regulate the emotional circuitry primarily at the level of the PAG.¹⁰

Lesions of the volitional pathway have been correlated with conditions of PBA, whereas direct activation of the emotional pathway tended to lead to emotional lability or the crying and laughing behaviors observed in dacrystic or gelastic epilepsy.¹⁰ The pivotal nature of the regulation occurring at the PAG has guided treatment options. Neurotransmitter receptors most closely associated with this region include glutamatergic N-methyl-d-aspartate (NMDA), muscarinic M1 to M3, γ-aminobutyric acid (GABA)-A, dopamine D2, norepinephrine α-1 and α-2, serotonin 5-HT1B/D, and sigma-1 receptors. Volitional inhibition of the PAG is mediated by acetylcholine and GABA balance at this location.¹⁰

When to screen for PBA

Ask the right question. PBA as a disease state likely has been widely under-reported, under-recognized, and misdiagnosed (typically, as a primary mood disorder).⁹ Three factors underscore this problem:

• Patients do not specifically report symptoms of affective disturbance (perhaps because they lack a vocabulary to separate concepts of mood and affect)
• Physicians do not ask patients about separations of mood and affect
• Perhaps most importantly, PBA lacks a general awareness and understanding.

Co-occurring mood disorders also may thwart PBA detection. One study of PBA in Alzheimer’s dementia found that 53% of patients with symptoms consistent with PBA also had a distinct mood disorder.¹⁷ This suggests that a PBA-specific screening test is needed for accurate diagnosis.

A single question might best refine the likelihood that a patient has PBA: “Do you ever cry for no reason?” In primary psychiatric illness, crying typically is associated with a specific trigger (eg, depressed mood, despair, anxiety). A patient’s inability to identify a trigger for crying suggests the pathological separation of mood and affect—the core of PBA, and worthy of further investigation.

Clinical rating scales that correlate to disease severity appear to be the most effective in identifying PBA. The PRISM study, to date the largest clinic-based study of PBA symptoms, used the Center for Neurologic Study-Liability Scale (CNS-LS) to gauge the presence and severity of PBA symptoms.¹ A 7-question, patient self-administered tool, the CNS-LS is graded on a 5-point Likert scale. A score ≥13 has high sensitivity and specificity for diagnosis of PBA, compared with physician diagnosis.

Another option, the 16-question Pathological Laughing and Crying Scale, is a clinician-administered screening tool. Again, a score ≥13 is consistent with symptoms required for a PBA diagnosis.

Treating PBA symptoms

Until recently, most pharmacotherapeutic interventions for PBA were based on off-label use of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). From 1980 to 2010, only 7 of 22 case reports or trials of TCAs or SSRIs for PBA were randomized, double-blind, and placebo-controlled. Five had 12 to 28 patients, and 2 had 106 and 128 patients, respectively. Only 1 controlled trial included a validated symptom severity scale, and none included a scale validated for PBA.¹⁸

In particular, imipramine and nortriptyline were studied for managing PBA in patients with stroke; amitriptyline, in patients with MS; and various SSRIs, in patients with stroke.¹¹ Response of PBA symptoms to antidepressant therapy was greater in all placebo-controlled trials than response to placebo.¹⁸ As seen in pharmacotherapy of depression, the lower burden of adverse effects and overall better tolerability of SSRIs resulted in their preferred use over TCAs. In some cases, the side effects of TCAs can be leveraged for therapeutic gain. If insomnia is a problem, a nighttime dose of a TCA could ameliorate this. Similarly, if a patient has sialorrhea, the anticholinergic effect of a TCA may show some benefit.¹⁹

Dextromethorphan plus quinidine. Dextromethorphan has long been of interest for a variety of neurodegenerative diseases. Studies of its efficacy were largely unsuccessful, however, because rapid metabolism by cytochrome P450 (CYP) 2D6 prevented CNS penetration.²⁰ Quinidine is an avid inhibitor of CYP2D6, even at very low dosages. Adding quinidine to dextromethorphan limits metabolism, allowing dextromethorphan to accumulate to a plasma concentration sufficient to penetrate the CNS.¹² In 2010, the combination agent dextromethorphan hydrobromide (20 mg)/quinidine (10 mg) (DM/Q) became the first treatment to receive FDA approval for managing PBA.¹¹

Mechanism of action. The exact mechanism of DM/Q in PBA remains unknown. Dextromethorphan is an agonist of sigma-1 receptors and a relatively specific noncompetitive antagonist of NMDA receptors. It also has been shown to modulate glutamate and serotonin neurotransmission and ion channel function.²⁰ Sigma-1 receptors are concentrated in the brainstem and parts of the cerebellum that are thought to coordinate motor emotional responses. Agonism of sigma-1 receptors on glutamatergic neurons has been proposed to limit release of glutamate from the presynaptic neuron while also limiting downstream transmission of glutamatergic signal in postsynaptic neurons.

Clinical trials. Two large trials have demonstrated efficacy of DM/Q in PBA. STAR was a 12-week, double-blind, placebo-controlled trial with 326 patients diagnosed with ALS or MS who showed PBA symptoms (CNS-LS score ≥13). Compared with placebo, DM/Q use was associated with significantly reduced (P < .01) daily episodes of PBA at 2, 4, 8, and 12 weeks.²⁰ The effect was rapid, with 30% fewer PBA episodes after the first week (P < .0167). At 12 weeks, 51% of patients on DM/Q had been symptom-free for at least 2 weeks.

The PRISM II study examined the efficacy of DM/Q in managing PBA in 102 individuals with dementia, 92 with stroke, and 67 with TBI. After 30 and 90 days, CNL-LS scores were significantly reduced (P < .001) compared with baseline scores.²⁰

Prescribing information. Dextro­methorphan—typically in the form of cough syrup—has been implicated as a substance of abuse. A placebo-controlled trial demonstrated that co-administering quinidine with dextromethorphan limits measures of positive reinforcement, such as euphoria and drug liking. This suggests that quinidine may be used to reduce abuse of dextromethorphan.²⁰ As such, the abuse potential of DM/Q appears to be low.

The most common adverse effects reported with DM/Q are diarrhea, dizziness, and cough.¹² Notably, patients who received DM/Q in the STAR trial were more likely to report dizziness than those receiving placebo (10.3% vs 5.5%), but patients receiving placebo were more likely to fall.^21,22

Package labeling warns that DM/Q causes dose-dependent QTc prolongation.²¹ Quinidine can be associated with significant QTc prolongation when dosed at antiarrhythmic levels, although mean plasma concentrations found with the 10 mg of quinidine in the approved DM/Q formulation are 1% to 3% of those associated with typical dosages used in antiarrhythmic therapy. Electrophysiology studies of quinidine 10 mg dosed every 12 hours have demonstrated a mean QTc increase at steady state of 6.8 milliseconds, compared with 9.1 milliseconds for a reference control (moxifloxacin).^12,21

Although this would seem to indicate a relatively low risk of clinically significant QTc prolongation at these ultra-low dosages of quinidine, it may be advisable to obtain an initial pre-dose and post-dose ECG and longitudinally monitor the QTc interval in patients with conditions that predispose to cardiac arrhythmias. Because quinidine inhibits CYP2D6, use caution when prescribing and monitoring other medications metabolized by this pathway.

Bottom Line

Pseudobulbar affect (PBA) is a disorder of affective expression that manifests as stereotyped and frequent outbursts of crying (not limited to lacrimation) or laughter. Symptoms are involuntary, uncontrolled, and exaggerated or incongruent with current mood. Episodes, lasting a few seconds to several minutes, may be unprovoked or occur in response to a mild stimulus, and patients typically display a normal affect between episodes.¹ PBA is estimated to affect 1 to 2 million people in the United States, although some studies suggest as many as 7 million,^1,2 depending on the evaluation method and threshold criteria used.³

 Where to look for pseudobulbar affect

 PBA has been most commonly described in 6 major  neurologic disorders:

• Alzheimer’s disease
• amyotrophic lateral sclerosis (ALS)
• multiple sclerosis (MS)
• Parkinson’s disease
• stroke
• traumatic brain injury (TBI).

Of these disorders, most studies have found the highest PBA prevalence in patients with ALS and TBI, with lesser (although significant) prevalence in Parkinson’s disease (Table 2).^1,12 These “big 6” diagnoses are not a comprehensive list, as many other disease states are associated with PBA (Table 3).^12-14

2 Pathways: ‘Generator’ and ‘governor’

Despite the many and varied injuries and illnesses associated with PBA, Lauterbach et al¹⁰ noted patterns that suggest dysregulation of 2 distinct but interconnected brain pathways: an emotional pathway controlled by a separate volitional pathway. Lesions to the volitional pathway (or its associated feedback or processing circuits) are thought to cause PBA symptoms.

To borrow an analogy from engineering, the emotional pathway is the “generator” of affect, whereas the volitional pathway is the “governor” of affect. Thus, injury to the “governor” results in overspill, or overflow, of affect that usually would be suppressed.

The emotional pathway, which coordinates the motor aspect of reflex laughing or crying, originates at the frontotemporal cortex, relaying to the amygdala and hypothalamus, then projecting to the dorsal brainstem, which includes the midbrain-pontine periaqueductal gray (PAG), dorsal tegmentum, and related brainstem.

The volitional pathway, which regulates the emotional pathway, originates in the dorsal and lateral frontoparietal cortex, projects through the internal capsule and midbrain basis pedunculi, and continues on to the anteroventral basis pontis. The basis pontis then serves as an afferent relay center for cerebellar activity. Projections from the pons then regulate the emotional circuitry primarily at the level of the PAG.¹⁰

Lesions of the volitional pathway have been correlated with conditions of PBA, whereas direct activation of the emotional pathway tended to lead to emotional lability or the crying and laughing behaviors observed in dacrystic or gelastic epilepsy.¹⁰ The pivotal nature of the regulation occurring at the PAG has guided treatment options. Neurotransmitter receptors most closely associated with this region include glutamatergic N-methyl-d-aspartate (NMDA), muscarinic M1 to M3, γ-aminobutyric acid (GABA)-A, dopamine D2, norepinephrine α-1 and α-2, serotonin 5-HT1B/D, and sigma-1 receptors. Volitional inhibition of the PAG is mediated by acetylcholine and GABA balance at this location.¹⁰

When to screen for PBA

Ask the right question. PBA as a disease state likely has been widely under-reported, under-recognized, and misdiagnosed (typically, as a primary mood disorder).⁹ Three factors underscore this problem:

• Patients do not specifically report symptoms of affective disturbance (perhaps because they lack a vocabulary to separate concepts of mood and affect)
• Physicians do not ask patients about separations of mood and affect
• Perhaps most importantly, PBA lacks a general awareness and understanding.

Co-occurring mood disorders also may thwart PBA detection. One study of PBA in Alzheimer’s dementia found that 53% of patients with symptoms consistent with PBA also had a distinct mood disorder.¹⁷ This suggests that a PBA-specific screening test is needed for accurate diagnosis.

A single question might best refine the likelihood that a patient has PBA: “Do you ever cry for no reason?” In primary psychiatric illness, crying typically is associated with a specific trigger (eg, depressed mood, despair, anxiety). A patient’s inability to identify a trigger for crying suggests the pathological separation of mood and affect—the core of PBA, and worthy of further investigation.

Clinical rating scales that correlate to disease severity appear to be the most effective in identifying PBA. The PRISM study, to date the largest clinic-based study of PBA symptoms, used the Center for Neurologic Study-Liability Scale (CNS-LS) to gauge the presence and severity of PBA symptoms.¹ A 7-question, patient self-administered tool, the CNS-LS is graded on a 5-point Likert scale. A score ≥13 has high sensitivity and specificity for diagnosis of PBA, compared with physician diagnosis.

Another option, the 16-question Pathological Laughing and Crying Scale, is a clinician-administered screening tool. Again, a score ≥13 is consistent with symptoms required for a PBA diagnosis.

Treating PBA symptoms

Until recently, most pharmacotherapeutic interventions for PBA were based on off-label use of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). From 1980 to 2010, only 7 of 22 case reports or trials of TCAs or SSRIs for PBA were randomized, double-blind, and placebo-controlled. Five had 12 to 28 patients, and 2 had 106 and 128 patients, respectively. Only 1 controlled trial included a validated symptom severity scale, and none included a scale validated for PBA.¹⁸

In particular, imipramine and nortriptyline were studied for managing PBA in patients with stroke; amitriptyline, in patients with MS; and various SSRIs, in patients with stroke.¹¹ Response of PBA symptoms to antidepressant therapy was greater in all placebo-controlled trials than response to placebo.¹⁸ As seen in pharmacotherapy of depression, the lower burden of adverse effects and overall better tolerability of SSRIs resulted in their preferred use over TCAs. In some cases, the side effects of TCAs can be leveraged for therapeutic gain. If insomnia is a problem, a nighttime dose of a TCA could ameliorate this. Similarly, if a patient has sialorrhea, the anticholinergic effect of a TCA may show some benefit.¹⁹

Dextromethorphan plus quinidine. Dextromethorphan has long been of interest for a variety of neurodegenerative diseases. Studies of its efficacy were largely unsuccessful, however, because rapid metabolism by cytochrome P450 (CYP) 2D6 prevented CNS penetration.²⁰ Quinidine is an avid inhibitor of CYP2D6, even at very low dosages. Adding quinidine to dextromethorphan limits metabolism, allowing dextromethorphan to accumulate to a plasma concentration sufficient to penetrate the CNS.¹² In 2010, the combination agent dextromethorphan hydrobromide (20 mg)/quinidine (10 mg) (DM/Q) became the first treatment to receive FDA approval for managing PBA.¹¹

Mechanism of action. The exact mechanism of DM/Q in PBA remains unknown. Dextromethorphan is an agonist of sigma-1 receptors and a relatively specific noncompetitive antagonist of NMDA receptors. It also has been shown to modulate glutamate and serotonin neurotransmission and ion channel function.²⁰ Sigma-1 receptors are concentrated in the brainstem and parts of the cerebellum that are thought to coordinate motor emotional responses. Agonism of sigma-1 receptors on glutamatergic neurons has been proposed to limit release of glutamate from the presynaptic neuron while also limiting downstream transmission of glutamatergic signal in postsynaptic neurons.

Clinical trials. Two large trials have demonstrated efficacy of DM/Q in PBA. STAR was a 12-week, double-blind, placebo-controlled trial with 326 patients diagnosed with ALS or MS who showed PBA symptoms (CNS-LS score ≥13). Compared with placebo, DM/Q use was associated with significantly reduced (P < .01) daily episodes of PBA at 2, 4, 8, and 12 weeks.²⁰ The effect was rapid, with 30% fewer PBA episodes after the first week (P < .0167). At 12 weeks, 51% of patients on DM/Q had been symptom-free for at least 2 weeks.

The PRISM II study examined the efficacy of DM/Q in managing PBA in 102 individuals with dementia, 92 with stroke, and 67 with TBI. After 30 and 90 days, CNL-LS scores were significantly reduced (P < .001) compared with baseline scores.²⁰

Prescribing information. Dextro­methorphan—typically in the form of cough syrup—has been implicated as a substance of abuse. A placebo-controlled trial demonstrated that co-administering quinidine with dextromethorphan limits measures of positive reinforcement, such as euphoria and drug liking. This suggests that quinidine may be used to reduce abuse of dextromethorphan.²⁰ As such, the abuse potential of DM/Q appears to be low.

The most common adverse effects reported with DM/Q are diarrhea, dizziness, and cough.¹² Notably, patients who received DM/Q in the STAR trial were more likely to report dizziness than those receiving placebo (10.3% vs 5.5%), but patients receiving placebo were more likely to fall.^21,22

Package labeling warns that DM/Q causes dose-dependent QTc prolongation.²¹ Quinidine can be associated with significant QTc prolongation when dosed at antiarrhythmic levels, although mean plasma concentrations found with the 10 mg of quinidine in the approved DM/Q formulation are 1% to 3% of those associated with typical dosages used in antiarrhythmic therapy. Electrophysiology studies of quinidine 10 mg dosed every 12 hours have demonstrated a mean QTc increase at steady state of 6.8 milliseconds, compared with 9.1 milliseconds for a reference control (moxifloxacin).^12,21

Although this would seem to indicate a relatively low risk of clinically significant QTc prolongation at these ultra-low dosages of quinidine, it may be advisable to obtain an initial pre-dose and post-dose ECG and longitudinally monitor the QTc interval in patients with conditions that predispose to cardiac arrhythmias. Because quinidine inhibits CYP2D6, use caution when prescribing and monitoring other medications metabolized by this pathway.

Bottom Line

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Most adults want to have happy romantic relationships. But meeting eligible companions and finding the time to date can feel nearly impossible to many physicians, especially residents, whose 80-hour work weeks limit opportunities to meet potential partners.¹

So it’s no surprise that Dr. R’s friends have suggested that she try online dating. If she does, she would be far from alone: 15% of U.S. adults have sought relationships online, and one-fourth of people in their 20s have used a mobile dating app.^2,3 Online dating might work well for Dr. R, too. Between 2005 and 2012, more than one-third of U.S. marriages started online, and these marriages seemed happier and ended in separation or divorce less often than marriages that started in more traditional ways.⁴

Online dating is just one example of how “the permeation of online and social media into everyday life is placing doctors in new situations that they find difficult to navigate.”⁵ Many physicians—psychiatrists among them—date online. Yet, like Dr. R, physicians are cautious about using social media because of worries about public exposure and legal concerns.⁵ Moreover, medical associations haven’t developed guidelines that would help physicians reconcile their professional and personal lives if they seek companionship online.⁶

Although we don’t have complete answers to Dr. R’s questions, we have gathered some ideas and information that she might find helpful. Read on as we explore:

• potential benefits for psychiatrists who try online dating
• problems when physicians use social media
• how to minimize mishaps if you seek companionship online.

Advantages and benefits

Online dating is most popular among young adults. But singles and divorcees of all ages, sexual orientations, and backgrounds are increasingly seeking long-term relationships with internet-based dating tools rather than hoping to meet people through family, friends, church, and the workplace. It has become common—and no longer stigmatizing—for couples to say they met online.^2,7

A dating Web site or app is a simple, fast, low-investment way to increase your opportunities to meet other singles and to make contact with more potential partners than you would meet otherwise. This is particularly helpful for people in thinner dating markets (eg, gays, lesbians, middle-age heterosexuals, and rural dwellers) or people seeking a companion of a particular type or lifestyle.^7,8 Many internet dating tools claim that their matching algorithms can increase your chances of meeting someone you will find compatible (although research questions whether the algorithms really work⁸). Dating sites and apps also let users engage in brief, computer-mediated communications that can foster greater attraction and comfort before meeting for a first date.⁸

Appeal to psychiatrists

Online dating may have special appeal to young psychiatrists such as Dr. R. Oddly enough, being a mental health professional can leave you socially isolated. Many people react cautiously when they learn you are a psychiatrist—they think you are evaluating them (and let’s face it: often, this is true).⁹ Psychiatrists should be cordial but circumspect in conducting work relationships, which limits the type and amount of social life they might generate in the setting where many people meet their future spouses.¹⁰

Online dating can help single psychiatrists overcome these barriers. Scientifically minded physicians can find plenty of research-grounded advice for improving online dating chances.^11-14 Two medical researchers even published a meta-analysis of evidence-based methods that can improve the chances of converting online contacts to a first date.¹⁵

Caution: Hazards ahead

When seeking romance online, psychiatrists shouldn’t forget their professional obligations, including the duty to maintain clear boundaries between their social and work lives.¹⁶ If Dr. R decides to try online dating, she will be making it possible for curious patients to gain access to some of her personal information. She will have to figure out how to avoid jeopardizing her professional reputation or inadvertently opening the door to sexual misconduct.¹⁷

Boundaries online. Psychiatrists use the term “boundaries” to refer to how they structure appointments and monitor their behavior during therapy to keep the treatment relationship free of personal, sexual, and romantic influences. Keeping one’s emotional life out of treatment helps prevent exploitation of patients and fosters a sense of safety and assurance that the physician is acting solely with the patient’s interest in mind. Breaching boundaries in ways that exploit patients or serve the doctor’s needs can undermine treatment, harm patients, and result in serious professional consequences.¹⁸

Maintaining appropriate boundaries can be challenging for psychiatrists who want to date online because the outside-the-office context can muddy the distinction between one’s professional and personal identity. Online dating environments make it easier for physicians to inadvertently initiate social or romantic interactions with people they have treated but don’t recognize (something the authors know has happened to colleagues). Additionally, the internet’s anonymity leaves users vulnerable to being lured into interactions with someone who is using a fictional online persona—an activity colloquially called “catfishing.”¹⁹

Although patients may play an active role in boundary breaches, the physician bears sole responsibility for maintaining proper limits within the therapeutic relationship.¹⁸ For many psychiatrists, innocuous but non-professional interactions with patients have been the first steps down a “slippery slope” toward serious boundary violations, including sexual contact—an activity that both the American Medical Association (AMA) and the American Psychiatric Association deem categorically unethical and that can lead to malpractice lawsuits, sanctions by medical license boards, and (in some jurisdictions) criminal prosecution.²⁰ When using social media and online dating tools, psychiatrists should avoid even seemingly minor boundary violations as a safeguard against more serious transgressions.^20,21

Reports of online misconduct by medical trainees and practitioners are plentiful.^22,23 In response, several medical organizations, including the AMA and the American College of Physicians, have developed professional guidelines for appropriate behavior on social media by physicians.^24,25 These guidelines stress the importance of maintaining a professional presence when one’s online activity is publicly viewable.

How much self-disclosure is appropriate?
Traditionally, psychiatrists (including psychoanalysts) have felt that occasional, limited, well-considered references to oneself are acceptable and even helpful in treatment.²⁶ The majority of therapists report using therapy-relevant self-disclosure, but they are cautious about what they say. Conscientious therapists avoid self-disclosure to satisfy their own needs, and they avoid self-disclosure with patients for whom it would have detrimental effects.^18,27

Dating Web sites contain a lot of personal information that physicians don’t usually share with patients. Although physicians who use social media are advised to be careful about the information they make available to the public,²⁸ this is more difficult to do with dating applications, where revealing some information about yourself is necessary for making meaningful connections. Creating an online dating profile means that you are potentially letting patients or patients’ relatives know about your place of residence, income, sexual orientation, number of children, and interests. You will need to think about how you will respond if a patient unexpectedly comments on your dating profile during a session or asks you out.

Beyond creating awkward situations, self-disclosure can have treatment implications, and it’s impossible to know how a particular comment will affect a particular client in a particular situation.²⁹ Psychiatrists who engage in online dating may want to limit their posted personal information only to what they would feel reasonably comfortable with having patients know about them, and hope this will suffice to capture the attention of potential partners.

Sustaining professionalism while remaining human. The term “medical professionalism” originally referred to ethical conduct during the practice of medicine³⁰ and to sustaining one’s commitment to patients, fellow professionals, and the institutions within which health care is provided.³¹ More recently, however, discussions of medical professionalism have encompassed how physicians comport themselves away from work. Physicians’ actions outside the office or hospital—and especially what they say, do, or post online—have a powerful effect on perceptions of their institutions and the medical profession as a whole.^25,32

Photos and comments posted by physicians can be seen by millions and can have major repercussions for employment prospects and public perceptions.²⁵ Questionable postings by physicians on social media outlets have resulted in disciplinary actions by licensing authorities and have damaged physicians’ careers.²³

What seems appropriate for a dating Web site varies from person to person. A suggestive smile or flirtatious joke that most people would find harmless may strike others as provocative. Derogatory language, depictions of intoxication or substance abuse, and inappropriate patient-related comments are clear-cut mistakes.^32-34 But also keep in mind that what medical professionals find acceptable to post on social networking sites does not always match what the general public thinks.³⁵

Bottom Line

Most adults want to have happy romantic relationships. But meeting eligible companions and finding the time to date can feel nearly impossible to many physicians, especially residents, whose 80-hour work weeks limit opportunities to meet potential partners.¹

So it’s no surprise that Dr. R’s friends have suggested that she try online dating. If she does, she would be far from alone: 15% of U.S. adults have sought relationships online, and one-fourth of people in their 20s have used a mobile dating app.^2,3 Online dating might work well for Dr. R, too. Between 2005 and 2012, more than one-third of U.S. marriages started online, and these marriages seemed happier and ended in separation or divorce less often than marriages that started in more traditional ways.⁴

Online dating is just one example of how “the permeation of online and social media into everyday life is placing doctors in new situations that they find difficult to navigate.”⁵ Many physicians—psychiatrists among them—date online. Yet, like Dr. R, physicians are cautious about using social media because of worries about public exposure and legal concerns.⁵ Moreover, medical associations haven’t developed guidelines that would help physicians reconcile their professional and personal lives if they seek companionship online.⁶

Although we don’t have complete answers to Dr. R’s questions, we have gathered some ideas and information that she might find helpful. Read on as we explore:

• potential benefits for psychiatrists who try online dating
• problems when physicians use social media
• how to minimize mishaps if you seek companionship online.

Advantages and benefits

Online dating is most popular among young adults. But singles and divorcees of all ages, sexual orientations, and backgrounds are increasingly seeking long-term relationships with internet-based dating tools rather than hoping to meet people through family, friends, church, and the workplace. It has become common—and no longer stigmatizing—for couples to say they met online.^2,7

A dating Web site or app is a simple, fast, low-investment way to increase your opportunities to meet other singles and to make contact with more potential partners than you would meet otherwise. This is particularly helpful for people in thinner dating markets (eg, gays, lesbians, middle-age heterosexuals, and rural dwellers) or people seeking a companion of a particular type or lifestyle.^7,8 Many internet dating tools claim that their matching algorithms can increase your chances of meeting someone you will find compatible (although research questions whether the algorithms really work⁸). Dating sites and apps also let users engage in brief, computer-mediated communications that can foster greater attraction and comfort before meeting for a first date.⁸

Appeal to psychiatrists

Online dating may have special appeal to young psychiatrists such as Dr. R. Oddly enough, being a mental health professional can leave you socially isolated. Many people react cautiously when they learn you are a psychiatrist—they think you are evaluating them (and let’s face it: often, this is true).⁹ Psychiatrists should be cordial but circumspect in conducting work relationships, which limits the type and amount of social life they might generate in the setting where many people meet their future spouses.¹⁰

Online dating can help single psychiatrists overcome these barriers. Scientifically minded physicians can find plenty of research-grounded advice for improving online dating chances.^11-14 Two medical researchers even published a meta-analysis of evidence-based methods that can improve the chances of converting online contacts to a first date.¹⁵

Caution: Hazards ahead

When seeking romance online, psychiatrists shouldn’t forget their professional obligations, including the duty to maintain clear boundaries between their social and work lives.¹⁶ If Dr. R decides to try online dating, she will be making it possible for curious patients to gain access to some of her personal information. She will have to figure out how to avoid jeopardizing her professional reputation or inadvertently opening the door to sexual misconduct.¹⁷

Boundaries online. Psychiatrists use the term “boundaries” to refer to how they structure appointments and monitor their behavior during therapy to keep the treatment relationship free of personal, sexual, and romantic influences. Keeping one’s emotional life out of treatment helps prevent exploitation of patients and fosters a sense of safety and assurance that the physician is acting solely with the patient’s interest in mind. Breaching boundaries in ways that exploit patients or serve the doctor’s needs can undermine treatment, harm patients, and result in serious professional consequences.¹⁸

Maintaining appropriate boundaries can be challenging for psychiatrists who want to date online because the outside-the-office context can muddy the distinction between one’s professional and personal identity. Online dating environments make it easier for physicians to inadvertently initiate social or romantic interactions with people they have treated but don’t recognize (something the authors know has happened to colleagues). Additionally, the internet’s anonymity leaves users vulnerable to being lured into interactions with someone who is using a fictional online persona—an activity colloquially called “catfishing.”¹⁹

Although patients may play an active role in boundary breaches, the physician bears sole responsibility for maintaining proper limits within the therapeutic relationship.¹⁸ For many psychiatrists, innocuous but non-professional interactions with patients have been the first steps down a “slippery slope” toward serious boundary violations, including sexual contact—an activity that both the American Medical Association (AMA) and the American Psychiatric Association deem categorically unethical and that can lead to malpractice lawsuits, sanctions by medical license boards, and (in some jurisdictions) criminal prosecution.²⁰ When using social media and online dating tools, psychiatrists should avoid even seemingly minor boundary violations as a safeguard against more serious transgressions.^20,21

Reports of online misconduct by medical trainees and practitioners are plentiful.^22,23 In response, several medical organizations, including the AMA and the American College of Physicians, have developed professional guidelines for appropriate behavior on social media by physicians.^24,25 These guidelines stress the importance of maintaining a professional presence when one’s online activity is publicly viewable.

How much self-disclosure is appropriate?
Traditionally, psychiatrists (including psychoanalysts) have felt that occasional, limited, well-considered references to oneself are acceptable and even helpful in treatment.²⁶ The majority of therapists report using therapy-relevant self-disclosure, but they are cautious about what they say. Conscientious therapists avoid self-disclosure to satisfy their own needs, and they avoid self-disclosure with patients for whom it would have detrimental effects.^18,27

Dating Web sites contain a lot of personal information that physicians don’t usually share with patients. Although physicians who use social media are advised to be careful about the information they make available to the public,²⁸ this is more difficult to do with dating applications, where revealing some information about yourself is necessary for making meaningful connections. Creating an online dating profile means that you are potentially letting patients or patients’ relatives know about your place of residence, income, sexual orientation, number of children, and interests. You will need to think about how you will respond if a patient unexpectedly comments on your dating profile during a session or asks you out.

Beyond creating awkward situations, self-disclosure can have treatment implications, and it’s impossible to know how a particular comment will affect a particular client in a particular situation.²⁹ Psychiatrists who engage in online dating may want to limit their posted personal information only to what they would feel reasonably comfortable with having patients know about them, and hope this will suffice to capture the attention of potential partners.

Sustaining professionalism while remaining human. The term “medical professionalism” originally referred to ethical conduct during the practice of medicine³⁰ and to sustaining one’s commitment to patients, fellow professionals, and the institutions within which health care is provided.³¹ More recently, however, discussions of medical professionalism have encompassed how physicians comport themselves away from work. Physicians’ actions outside the office or hospital—and especially what they say, do, or post online—have a powerful effect on perceptions of their institutions and the medical profession as a whole.^25,32

Photos and comments posted by physicians can be seen by millions and can have major repercussions for employment prospects and public perceptions.²⁵ Questionable postings by physicians on social media outlets have resulted in disciplinary actions by licensing authorities and have damaged physicians’ careers.²³

What seems appropriate for a dating Web site varies from person to person. A suggestive smile or flirtatious joke that most people would find harmless may strike others as provocative. Derogatory language, depictions of intoxication or substance abuse, and inappropriate patient-related comments are clear-cut mistakes.^32-34 But also keep in mind that what medical professionals find acceptable to post on social networking sites does not always match what the general public thinks.³⁵

Bottom Line

Most adults want to have happy romantic relationships. But meeting eligible companions and finding the time to date can feel nearly impossible to many physicians, especially residents, whose 80-hour work weeks limit opportunities to meet potential partners.¹

So it’s no surprise that Dr. R’s friends have suggested that she try online dating. If she does, she would be far from alone: 15% of U.S. adults have sought relationships online, and one-fourth of people in their 20s have used a mobile dating app.^2,3 Online dating might work well for Dr. R, too. Between 2005 and 2012, more than one-third of U.S. marriages started online, and these marriages seemed happier and ended in separation or divorce less often than marriages that started in more traditional ways.⁴

Online dating is just one example of how “the permeation of online and social media into everyday life is placing doctors in new situations that they find difficult to navigate.”⁵ Many physicians—psychiatrists among them—date online. Yet, like Dr. R, physicians are cautious about using social media because of worries about public exposure and legal concerns.⁵ Moreover, medical associations haven’t developed guidelines that would help physicians reconcile their professional and personal lives if they seek companionship online.⁶

Although we don’t have complete answers to Dr. R’s questions, we have gathered some ideas and information that she might find helpful. Read on as we explore:

• potential benefits for psychiatrists who try online dating
• problems when physicians use social media
• how to minimize mishaps if you seek companionship online.

Advantages and benefits

Online dating is most popular among young adults. But singles and divorcees of all ages, sexual orientations, and backgrounds are increasingly seeking long-term relationships with internet-based dating tools rather than hoping to meet people through family, friends, church, and the workplace. It has become common—and no longer stigmatizing—for couples to say they met online.^2,7

A dating Web site or app is a simple, fast, low-investment way to increase your opportunities to meet other singles and to make contact with more potential partners than you would meet otherwise. This is particularly helpful for people in thinner dating markets (eg, gays, lesbians, middle-age heterosexuals, and rural dwellers) or people seeking a companion of a particular type or lifestyle.^7,8 Many internet dating tools claim that their matching algorithms can increase your chances of meeting someone you will find compatible (although research questions whether the algorithms really work⁸). Dating sites and apps also let users engage in brief, computer-mediated communications that can foster greater attraction and comfort before meeting for a first date.⁸

Appeal to psychiatrists

Online dating may have special appeal to young psychiatrists such as Dr. R. Oddly enough, being a mental health professional can leave you socially isolated. Many people react cautiously when they learn you are a psychiatrist—they think you are evaluating them (and let’s face it: often, this is true).⁹ Psychiatrists should be cordial but circumspect in conducting work relationships, which limits the type and amount of social life they might generate in the setting where many people meet their future spouses.¹⁰

Online dating can help single psychiatrists overcome these barriers. Scientifically minded physicians can find plenty of research-grounded advice for improving online dating chances.^11-14 Two medical researchers even published a meta-analysis of evidence-based methods that can improve the chances of converting online contacts to a first date.¹⁵

Caution: Hazards ahead

When seeking romance online, psychiatrists shouldn’t forget their professional obligations, including the duty to maintain clear boundaries between their social and work lives.¹⁶ If Dr. R decides to try online dating, she will be making it possible for curious patients to gain access to some of her personal information. She will have to figure out how to avoid jeopardizing her professional reputation or inadvertently opening the door to sexual misconduct.¹⁷

Boundaries online. Psychiatrists use the term “boundaries” to refer to how they structure appointments and monitor their behavior during therapy to keep the treatment relationship free of personal, sexual, and romantic influences. Keeping one’s emotional life out of treatment helps prevent exploitation of patients and fosters a sense of safety and assurance that the physician is acting solely with the patient’s interest in mind. Breaching boundaries in ways that exploit patients or serve the doctor’s needs can undermine treatment, harm patients, and result in serious professional consequences.¹⁸

Maintaining appropriate boundaries can be challenging for psychiatrists who want to date online because the outside-the-office context can muddy the distinction between one’s professional and personal identity. Online dating environments make it easier for physicians to inadvertently initiate social or romantic interactions with people they have treated but don’t recognize (something the authors know has happened to colleagues). Additionally, the internet’s anonymity leaves users vulnerable to being lured into interactions with someone who is using a fictional online persona—an activity colloquially called “catfishing.”¹⁹

Although patients may play an active role in boundary breaches, the physician bears sole responsibility for maintaining proper limits within the therapeutic relationship.¹⁸ For many psychiatrists, innocuous but non-professional interactions with patients have been the first steps down a “slippery slope” toward serious boundary violations, including sexual contact—an activity that both the American Medical Association (AMA) and the American Psychiatric Association deem categorically unethical and that can lead to malpractice lawsuits, sanctions by medical license boards, and (in some jurisdictions) criminal prosecution.²⁰ When using social media and online dating tools, psychiatrists should avoid even seemingly minor boundary violations as a safeguard against more serious transgressions.^20,21

Reports of online misconduct by medical trainees and practitioners are plentiful.^22,23 In response, several medical organizations, including the AMA and the American College of Physicians, have developed professional guidelines for appropriate behavior on social media by physicians.^24,25 These guidelines stress the importance of maintaining a professional presence when one’s online activity is publicly viewable.

How much self-disclosure is appropriate?
Traditionally, psychiatrists (including psychoanalysts) have felt that occasional, limited, well-considered references to oneself are acceptable and even helpful in treatment.²⁶ The majority of therapists report using therapy-relevant self-disclosure, but they are cautious about what they say. Conscientious therapists avoid self-disclosure to satisfy their own needs, and they avoid self-disclosure with patients for whom it would have detrimental effects.^18,27

Dating Web sites contain a lot of personal information that physicians don’t usually share with patients. Although physicians who use social media are advised to be careful about the information they make available to the public,²⁸ this is more difficult to do with dating applications, where revealing some information about yourself is necessary for making meaningful connections. Creating an online dating profile means that you are potentially letting patients or patients’ relatives know about your place of residence, income, sexual orientation, number of children, and interests. You will need to think about how you will respond if a patient unexpectedly comments on your dating profile during a session or asks you out.

Beyond creating awkward situations, self-disclosure can have treatment implications, and it’s impossible to know how a particular comment will affect a particular client in a particular situation.²⁹ Psychiatrists who engage in online dating may want to limit their posted personal information only to what they would feel reasonably comfortable with having patients know about them, and hope this will suffice to capture the attention of potential partners.

Sustaining professionalism while remaining human. The term “medical professionalism” originally referred to ethical conduct during the practice of medicine³⁰ and to sustaining one’s commitment to patients, fellow professionals, and the institutions within which health care is provided.³¹ More recently, however, discussions of medical professionalism have encompassed how physicians comport themselves away from work. Physicians’ actions outside the office or hospital—and especially what they say, do, or post online—have a powerful effect on perceptions of their institutions and the medical profession as a whole.^25,32

Photos and comments posted by physicians can be seen by millions and can have major repercussions for employment prospects and public perceptions.²⁵ Questionable postings by physicians on social media outlets have resulted in disciplinary actions by licensing authorities and have damaged physicians’ careers.²³

What seems appropriate for a dating Web site varies from person to person. A suggestive smile or flirtatious joke that most people would find harmless may strike others as provocative. Derogatory language, depictions of intoxication or substance abuse, and inappropriate patient-related comments are clear-cut mistakes.^32-34 But also keep in mind that what medical professionals find acceptable to post on social networking sites does not always match what the general public thinks.³⁵

Bottom Line

Pharmacogenomics—the study of how genetic variability influences drug response—is increasingly being used to personalize pharmacotherapy. Used in the context of other clinical variables, genetic-based drug selection and dosing could help clinicians choose the right therapy for a patient, thus minimizing the incidence of treatment failure and intolerable side effects. Pharmacogenomics could be particularly useful in psychiatric pharmacotherapy, where response rates are low and the risk of adverse effects and nonadherence is high.

Despite the potential benefits of pharmacogenetic testing, many barriers prevent its routine use in practice, including a lack of knowledge about how to (1) order gene tests, (2) interpret results for an individual patient, and (3) apply those results to care. To help bridge this knowledge gap, we list practical, freely available pharmacogenomics resources that a psychiatric practitioner can use.

CPIC guidelines

The Clinical Pharmacogenetics Implement­ation Consortium (CPIC) is an international collaboration of pharmacogenomics experts that publishes clinical practice guidelines on using pharmacogenetic test results to optimize drug therapy.¹ Note: These guidelines do not address when tests should be ordered, but rather how results should be used to guide prescribing.

• how to convert genotype to phenotype
• how to modify drug selection or dosing based on these results
• the level of evidence for each recommendation.

CPIC guidelines and supplementary information are available on the CPIC Web site (https://www.cpicpgx.org) and are updated regularly. Table 1 provides current CPIC guidelines for neuropsychiatric drugs.

PharmGKB

Providing searchable annotations of pharmacogenetic variants, PharmGKB summarizes the clinical implications of important pharmacogenes, and includes FDA drug labels containing pharmacogenomics information (https://www.pharmgkb.org).² The Web site also provides users with evidence-based figures illustrating the pharmacokinetic and pharmacodynamic pathways of drugs that have pharmacogenetic implications.

PharmGKB is an excellent resource to consult for a summary of available evidence when a CPIC guideline does not exist for a given gene or drug.

Other resources

Table 2^3-8 lists other online resources for practitioners to aid in advancing pharmacogenomics knowledge as it relates to practice.

Putting guidance to best use

Familiarity with resources such as CPIC guidelines and PharmGKB can help ensure that patients with pharmacogenetic test results receive genetically tailored therapy that is more likely to be effective and less likely to cause adverse effects.^9,10

Pharmacogenomics—the study of how genetic variability influences drug response—is increasingly being used to personalize pharmacotherapy. Used in the context of other clinical variables, genetic-based drug selection and dosing could help clinicians choose the right therapy for a patient, thus minimizing the incidence of treatment failure and intolerable side effects. Pharmacogenomics could be particularly useful in psychiatric pharmacotherapy, where response rates are low and the risk of adverse effects and nonadherence is high.

Despite the potential benefits of pharmacogenetic testing, many barriers prevent its routine use in practice, including a lack of knowledge about how to (1) order gene tests, (2) interpret results for an individual patient, and (3) apply those results to care. To help bridge this knowledge gap, we list practical, freely available pharmacogenomics resources that a psychiatric practitioner can use.

CPIC guidelines

The Clinical Pharmacogenetics Implement­ation Consortium (CPIC) is an international collaboration of pharmacogenomics experts that publishes clinical practice guidelines on using pharmacogenetic test results to optimize drug therapy.¹ Note: These guidelines do not address when tests should be ordered, but rather how results should be used to guide prescribing.

• how to convert genotype to phenotype
• how to modify drug selection or dosing based on these results
• the level of evidence for each recommendation.

CPIC guidelines and supplementary information are available on the CPIC Web site (https://www.cpicpgx.org) and are updated regularly. Table 1 provides current CPIC guidelines for neuropsychiatric drugs.

PharmGKB

Providing searchable annotations of pharmacogenetic variants, PharmGKB summarizes the clinical implications of important pharmacogenes, and includes FDA drug labels containing pharmacogenomics information (https://www.pharmgkb.org).² The Web site also provides users with evidence-based figures illustrating the pharmacokinetic and pharmacodynamic pathways of drugs that have pharmacogenetic implications.

PharmGKB is an excellent resource to consult for a summary of available evidence when a CPIC guideline does not exist for a given gene or drug.

Other resources

Table 2^3-8 lists other online resources for practitioners to aid in advancing pharmacogenomics knowledge as it relates to practice.

Putting guidance to best use

Familiarity with resources such as CPIC guidelines and PharmGKB can help ensure that patients with pharmacogenetic test results receive genetically tailored therapy that is more likely to be effective and less likely to cause adverse effects.^9,10

Pharmacogenomics—the study of how genetic variability influences drug response—is increasingly being used to personalize pharmacotherapy. Used in the context of other clinical variables, genetic-based drug selection and dosing could help clinicians choose the right therapy for a patient, thus minimizing the incidence of treatment failure and intolerable side effects. Pharmacogenomics could be particularly useful in psychiatric pharmacotherapy, where response rates are low and the risk of adverse effects and nonadherence is high.

Despite the potential benefits of pharmacogenetic testing, many barriers prevent its routine use in practice, including a lack of knowledge about how to (1) order gene tests, (2) interpret results for an individual patient, and (3) apply those results to care. To help bridge this knowledge gap, we list practical, freely available pharmacogenomics resources that a psychiatric practitioner can use.

CPIC guidelines

The Clinical Pharmacogenetics Implement­ation Consortium (CPIC) is an international collaboration of pharmacogenomics experts that publishes clinical practice guidelines on using pharmacogenetic test results to optimize drug therapy.¹ Note: These guidelines do not address when tests should be ordered, but rather how results should be used to guide prescribing.

• how to convert genotype to phenotype
• how to modify drug selection or dosing based on these results
• the level of evidence for each recommendation.

CPIC guidelines and supplementary information are available on the CPIC Web site (https://www.cpicpgx.org) and are updated regularly. Table 1 provides current CPIC guidelines for neuropsychiatric drugs.

PharmGKB

Providing searchable annotations of pharmacogenetic variants, PharmGKB summarizes the clinical implications of important pharmacogenes, and includes FDA drug labels containing pharmacogenomics information (https://www.pharmgkb.org).² The Web site also provides users with evidence-based figures illustrating the pharmacokinetic and pharmacodynamic pathways of drugs that have pharmacogenetic implications.

PharmGKB is an excellent resource to consult for a summary of available evidence when a CPIC guideline does not exist for a given gene or drug.

Other resources

Table 2^3-8 lists other online resources for practitioners to aid in advancing pharmacogenomics knowledge as it relates to practice.

Putting guidance to best use

Familiarity with resources such as CPIC guidelines and PharmGKB can help ensure that patients with pharmacogenetic test results receive genetically tailored therapy that is more likely to be effective and less likely to cause adverse effects.^9,10

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.

Ketamine, a high-affinity, noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist, is used in human and veterinary medicine for its anesthetic and analgesic properties.¹ NMDA receptors could trigger cellular and behavioral responses, and ketamine blocks neuronal communication pathways.

How ketamine works

Water- and lipid-soluble, ketamine is available in oral, topical, IM, and IV forms. Plasma concentrations reach maximum levels minutes after IV infusion; 5 to 15 minutes after IM administration; and 30 minutes after oral ingestion.¹ The duration of action is as long as 2 hours after IM injection, and 4 to 6 hours orally. Metabolites are eliminated in urine.

Ketamine, co-prescribed with stimulants and some antidepressant drugs, can induce unwanted effects, such as increased blood pressure. Auditory and visual hallucinations are reported occasionally, especially in patients receiving a high dosage or in those with alcohol dependence.¹ Hypertension, tachycardia, cardiac arrhythmia, and pain at injection site are the most common adverse effects.

Some advantages over ECT in treating depression

The efficacy of electroconvulsive therapy (ECT) in alleviating depression depends on seizure duration. Compared with methohexital, an anesthetic used for ECT, ketamine offers some advantages:

• increased ictal time
• augmented mid-ictal slow-wave amplitude
• shortened post-treatment re-orientation time
• less cognitive dysfunction.²

Uses for ketamine

Treatment-resistant depression. The glutamatergic system is implicated in depression.^2,3 Ketamine works in patients with treatment-resistant depression by blocking glutamate NMDA receptors and increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, resulting in a rapid, sustained antidepressant effect. Response to ketamine occurs within 2 hours and lasts approximately 1 week.

Abuse potential

There is documented risk of ketamine abuse. It may create psychedelic effects that some people find pleasurable, such as sedation, disinhibition, and altered perceptions.⁶ There also may be a component of physiological dependence.⁶

Conclusion

Ketamine’s rapid antidepressant effect results could be beneficial when used in severely depressed and suicidal patients. Given the potential risks of ketamine, safety considerations will determine whether this drug is successful as a therapy for people with a mood disorder.

Further research about ketamine usage including pain management and affective disorders is anticipated.⁷ Investigations substantiating relative safety and clinical trials are still on-going.⁸

Related Resources
• Nichols SD, Bishop J. Is the evidence compelling for using ketamine to treat resistant depression? Current Psychiatry. 2015;15(5):48-51.
• National Institute of Mental Health. Highlight: ketamine: a new (and faster) path to treating depression. www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-ketamine-a-new-and-faster-path-to-treatingdepression.shtml.

A psychiatric consultation service in an academic medical center usually is a robust and busy setting. In addition to expert faculty, the service is staffed by trainees (psychosomatic medicine fellows and psychiatry residents), nurse practitioners, and medical students. I have been drawn to this growing field, which is evolving hand in hand with advances in medical therapy (eg, new antineoplastic, antiretroviral, and anticonvulsant regimens) and surgical intervention (eg, heart, lung, and gut transplantation).

As a consultant, I have learned that we have an obligation to a dual clientele:

• the patient, through an established doctor–patient relationship
• the primary team, which requires our assistance or raises questions about management.

While working as a trainee in providing psychiatric consultative services, I have noted a number of ethical challenges that consultants face. Below are noteworthy examples.

Justice: Is less, more?

We live in an era of growing advocacy of the recognition, acceptance, and treatment of mental illness.¹ However, there does not appear to be enough psychiatric providers for the American population.² Regrettably, a timely psychiatric assessment is, for many, a unaffordable luxury; in some regions of the United States, the wait for an outpatient psychiatric appointment is longer than 6 months.³

When a patient is admitted to the hospital, admitting physicians often consider ordering a psychiatric consult if they suspect an underlying psychiatric disorder or if they would like an expert’s opinion on some matter—such as (1) medications already prescribed for the patient as an outpatient and (2) a patient’s decision-making capacity in complex situations—without reflecting on how much of a commodity this expert opinion is. (After all, in an ideal world, concerns about cost shouldn’t factor in to what we offer our patients.)

Different practitioners have different thresholds for requesting a psychiatric consultation; no clear guidelines or recommendations exist as to how to “calibrate” one’s self to be a good consultee. As psychiatrists, we rarely call for a cardiology consult just because a patient is hypertensive and takes a diuretic at home, or call in an orthopedic surgeon because a patient with a history of arthroplasty has knee pain today. Sometimes, however, it seems to me that our non-psychiatry colleagues don’t think twice to ask for our services if their patients have a history of mental illness, even if it’s well controlled.

There is no winning formula for calculating how many psychiatric providers and resources (represented by the clinical currencies of, respectively, full-time equivalents and relative value units) a consultation service should have, but efforts have been made to solve this mystery.⁴ Some institutions track, with different methods and variable accuracy, the number of consults they provide annually; others wing it. Lack of accuracy and standardization means that the system is prone to sacrificing quality for quantity in the provision of services, and to provide services in an inconsistent manner (think: better quality on slower days).

Nonmaleficence: Good intentions…

Within the U.S. health care system, a consulting psychiatrist must diagnose a billable condition to be reimbursed for a consult. But what if a so-called soft consult is requested and, after the evaluation, a major mental disorder that warranted our time and expertise can’t be identified?

That situation places the provider in an awkward position. Up-diagnosing might seem like a necessity to ensure reimbursement but, in a society that still stigmatizes mental illness, the health risks of charting a major mental disorder (and prescribing a vaguely warranted psychotropic) might outweigh the benefits for some patients, in the long run.

Coding systems can impact and complicate this scenario even more. We are required to comply with coding systems by providing as many predetermined historical and clinical details of any specific major mental disorder as we can document. As we become more detail-oriented, I wonder if we are losing touch with the reality of our patients’ suffering and deviating from the human emotional experience, as we focus on complying with the health care system and maximizing hospital reimbursement.

Beneficence: The care you would want for your loved ones

For me, an attractive aspect of becoming a psychiatric consultant in the medical setting was to function as a mental health ambassador, so to speak. We often evaluate patients who have never seen a psychiatrist before (eg, when there are symptoms of acute stress disorder in a trauma patient or postoperative delirium in a patient who does not have a psychiatric history). On those occasions, we have the opportunity to make an effective, long-lasting intervention with our clinical encounter, accurate diagnosis, medication recommendations, and outpatient referrals.

Sometimes, the best follow-up plans and intentions are undone by uneven discharge coordination efforts and limited community resources. Some medical institutions have become better at tracking reasons for re-hospitalization and at making post-discharge telephone calls to support good transition to outpatient services. Often, it is necessary to call on nonprofit organizations and public institutions to provide referral and crisis services, but we can always do a better job at offering our patients a comprehensive mental health treatment plan, even from the consultation arena.

Autonomy: Who is in control?

Psychiatry provides varying levels of intervention for acutely mentally ill patients. Laws and criteria for involuntary commitment and the use of psychotropic medication under such circumstances vary from state to state.⁵

In the consultation-liaison setting, we often co-manage patients with a neuropsychiatric disorder that precludes them from participating fully in medical decisions. Other times, patients come to our attention involuntarily (eg, by way of medical admission) having a high level of premorbid autonomy: They make their own life decisions, choose not to engage in psychiatric treatment, administer their funds (when they have them), and so on.

Complex ethical situations can arise when (1) there is disagreement between physician and patient and (2) payment for care or insurance coverage plays a role in disposition plans or long-term placement. Public institutions might have a modus operandi that allows for extra room to deliberate and keep the treatment conversation going—more so than for-profit health centers, where financial forces can sway providers’ judgment toward autonomy, regardless of what is best for the patient.

Summing up: Let’s be Hippocratic psychiatrists

As many forces continue to influence the way we practice the art and science of medicine and psychiatry, it’s important to pay close attention to ongoing challenges and utilize organized medicine to advocate for better ways of running an effective consultation service in an ethical manner. As a trainee and future psychosomatic medicine psychiatrist, I am committed to starting these conversations wherever I go.

We need novel ways to look at, question, understand, study, and review our clinical practice to effectively tackle these challenges as we continue advancing as a field.

A psychiatric consultation service in an academic medical center usually is a robust and busy setting. In addition to expert faculty, the service is staffed by trainees (psychosomatic medicine fellows and psychiatry residents), nurse practitioners, and medical students. I have been drawn to this growing field, which is evolving hand in hand with advances in medical therapy (eg, new antineoplastic, antiretroviral, and anticonvulsant regimens) and surgical intervention (eg, heart, lung, and gut transplantation).

As a consultant, I have learned that we have an obligation to a dual clientele:

• the patient, through an established doctor–patient relationship
• the primary team, which requires our assistance or raises questions about management.

While working as a trainee in providing psychiatric consultative services, I have noted a number of ethical challenges that consultants face. Below are noteworthy examples.

Justice: Is less, more?

We live in an era of growing advocacy of the recognition, acceptance, and treatment of mental illness.¹ However, there does not appear to be enough psychiatric providers for the American population.² Regrettably, a timely psychiatric assessment is, for many, a unaffordable luxury; in some regions of the United States, the wait for an outpatient psychiatric appointment is longer than 6 months.³

When a patient is admitted to the hospital, admitting physicians often consider ordering a psychiatric consult if they suspect an underlying psychiatric disorder or if they would like an expert’s opinion on some matter—such as (1) medications already prescribed for the patient as an outpatient and (2) a patient’s decision-making capacity in complex situations—without reflecting on how much of a commodity this expert opinion is. (After all, in an ideal world, concerns about cost shouldn’t factor in to what we offer our patients.)

Different practitioners have different thresholds for requesting a psychiatric consultation; no clear guidelines or recommendations exist as to how to “calibrate” one’s self to be a good consultee. As psychiatrists, we rarely call for a cardiology consult just because a patient is hypertensive and takes a diuretic at home, or call in an orthopedic surgeon because a patient with a history of arthroplasty has knee pain today. Sometimes, however, it seems to me that our non-psychiatry colleagues don’t think twice to ask for our services if their patients have a history of mental illness, even if it’s well controlled.

There is no winning formula for calculating how many psychiatric providers and resources (represented by the clinical currencies of, respectively, full-time equivalents and relative value units) a consultation service should have, but efforts have been made to solve this mystery.⁴ Some institutions track, with different methods and variable accuracy, the number of consults they provide annually; others wing it. Lack of accuracy and standardization means that the system is prone to sacrificing quality for quantity in the provision of services, and to provide services in an inconsistent manner (think: better quality on slower days).

Nonmaleficence: Good intentions…

Within the U.S. health care system, a consulting psychiatrist must diagnose a billable condition to be reimbursed for a consult. But what if a so-called soft consult is requested and, after the evaluation, a major mental disorder that warranted our time and expertise can’t be identified?

That situation places the provider in an awkward position. Up-diagnosing might seem like a necessity to ensure reimbursement but, in a society that still stigmatizes mental illness, the health risks of charting a major mental disorder (and prescribing a vaguely warranted psychotropic) might outweigh the benefits for some patients, in the long run.

Coding systems can impact and complicate this scenario even more. We are required to comply with coding systems by providing as many predetermined historical and clinical details of any specific major mental disorder as we can document. As we become more detail-oriented, I wonder if we are losing touch with the reality of our patients’ suffering and deviating from the human emotional experience, as we focus on complying with the health care system and maximizing hospital reimbursement.

Beneficence: The care you would want for your loved ones

For me, an attractive aspect of becoming a psychiatric consultant in the medical setting was to function as a mental health ambassador, so to speak. We often evaluate patients who have never seen a psychiatrist before (eg, when there are symptoms of acute stress disorder in a trauma patient or postoperative delirium in a patient who does not have a psychiatric history). On those occasions, we have the opportunity to make an effective, long-lasting intervention with our clinical encounter, accurate diagnosis, medication recommendations, and outpatient referrals.

Sometimes, the best follow-up plans and intentions are undone by uneven discharge coordination efforts and limited community resources. Some medical institutions have become better at tracking reasons for re-hospitalization and at making post-discharge telephone calls to support good transition to outpatient services. Often, it is necessary to call on nonprofit organizations and public institutions to provide referral and crisis services, but we can always do a better job at offering our patients a comprehensive mental health treatment plan, even from the consultation arena.

Autonomy: Who is in control?

Psychiatry provides varying levels of intervention for acutely mentally ill patients. Laws and criteria for involuntary commitment and the use of psychotropic medication under such circumstances vary from state to state.⁵

In the consultation-liaison setting, we often co-manage patients with a neuropsychiatric disorder that precludes them from participating fully in medical decisions. Other times, patients come to our attention involuntarily (eg, by way of medical admission) having a high level of premorbid autonomy: They make their own life decisions, choose not to engage in psychiatric treatment, administer their funds (when they have them), and so on.

Complex ethical situations can arise when (1) there is disagreement between physician and patient and (2) payment for care or insurance coverage plays a role in disposition plans or long-term placement. Public institutions might have a modus operandi that allows for extra room to deliberate and keep the treatment conversation going—more so than for-profit health centers, where financial forces can sway providers’ judgment toward autonomy, regardless of what is best for the patient.

Summing up: Let’s be Hippocratic psychiatrists

As many forces continue to influence the way we practice the art and science of medicine and psychiatry, it’s important to pay close attention to ongoing challenges and utilize organized medicine to advocate for better ways of running an effective consultation service in an ethical manner. As a trainee and future psychosomatic medicine psychiatrist, I am committed to starting these conversations wherever I go.

We need novel ways to look at, question, understand, study, and review our clinical practice to effectively tackle these challenges as we continue advancing as a field.

A psychiatric consultation service in an academic medical center usually is a robust and busy setting. In addition to expert faculty, the service is staffed by trainees (psychosomatic medicine fellows and psychiatry residents), nurse practitioners, and medical students. I have been drawn to this growing field, which is evolving hand in hand with advances in medical therapy (eg, new antineoplastic, antiretroviral, and anticonvulsant regimens) and surgical intervention (eg, heart, lung, and gut transplantation).

As a consultant, I have learned that we have an obligation to a dual clientele:

• the patient, through an established doctor–patient relationship
• the primary team, which requires our assistance or raises questions about management.

While working as a trainee in providing psychiatric consultative services, I have noted a number of ethical challenges that consultants face. Below are noteworthy examples.

Justice: Is less, more?

We live in an era of growing advocacy of the recognition, acceptance, and treatment of mental illness.¹ However, there does not appear to be enough psychiatric providers for the American population.² Regrettably, a timely psychiatric assessment is, for many, a unaffordable luxury; in some regions of the United States, the wait for an outpatient psychiatric appointment is longer than 6 months.³

When a patient is admitted to the hospital, admitting physicians often consider ordering a psychiatric consult if they suspect an underlying psychiatric disorder or if they would like an expert’s opinion on some matter—such as (1) medications already prescribed for the patient as an outpatient and (2) a patient’s decision-making capacity in complex situations—without reflecting on how much of a commodity this expert opinion is. (After all, in an ideal world, concerns about cost shouldn’t factor in to what we offer our patients.)

Different practitioners have different thresholds for requesting a psychiatric consultation; no clear guidelines or recommendations exist as to how to “calibrate” one’s self to be a good consultee. As psychiatrists, we rarely call for a cardiology consult just because a patient is hypertensive and takes a diuretic at home, or call in an orthopedic surgeon because a patient with a history of arthroplasty has knee pain today. Sometimes, however, it seems to me that our non-psychiatry colleagues don’t think twice to ask for our services if their patients have a history of mental illness, even if it’s well controlled.

There is no winning formula for calculating how many psychiatric providers and resources (represented by the clinical currencies of, respectively, full-time equivalents and relative value units) a consultation service should have, but efforts have been made to solve this mystery.⁴ Some institutions track, with different methods and variable accuracy, the number of consults they provide annually; others wing it. Lack of accuracy and standardization means that the system is prone to sacrificing quality for quantity in the provision of services, and to provide services in an inconsistent manner (think: better quality on slower days).

Nonmaleficence: Good intentions…

Within the U.S. health care system, a consulting psychiatrist must diagnose a billable condition to be reimbursed for a consult. But what if a so-called soft consult is requested and, after the evaluation, a major mental disorder that warranted our time and expertise can’t be identified?

That situation places the provider in an awkward position. Up-diagnosing might seem like a necessity to ensure reimbursement but, in a society that still stigmatizes mental illness, the health risks of charting a major mental disorder (and prescribing a vaguely warranted psychotropic) might outweigh the benefits for some patients, in the long run.

Coding systems can impact and complicate this scenario even more. We are required to comply with coding systems by providing as many predetermined historical and clinical details of any specific major mental disorder as we can document. As we become more detail-oriented, I wonder if we are losing touch with the reality of our patients’ suffering and deviating from the human emotional experience, as we focus on complying with the health care system and maximizing hospital reimbursement.

Beneficence: The care you would want for your loved ones

For me, an attractive aspect of becoming a psychiatric consultant in the medical setting was to function as a mental health ambassador, so to speak. We often evaluate patients who have never seen a psychiatrist before (eg, when there are symptoms of acute stress disorder in a trauma patient or postoperative delirium in a patient who does not have a psychiatric history). On those occasions, we have the opportunity to make an effective, long-lasting intervention with our clinical encounter, accurate diagnosis, medication recommendations, and outpatient referrals.

Sometimes, the best follow-up plans and intentions are undone by uneven discharge coordination efforts and limited community resources. Some medical institutions have become better at tracking reasons for re-hospitalization and at making post-discharge telephone calls to support good transition to outpatient services. Often, it is necessary to call on nonprofit organizations and public institutions to provide referral and crisis services, but we can always do a better job at offering our patients a comprehensive mental health treatment plan, even from the consultation arena.

Autonomy: Who is in control?

Psychiatry provides varying levels of intervention for acutely mentally ill patients. Laws and criteria for involuntary commitment and the use of psychotropic medication under such circumstances vary from state to state.⁵

In the consultation-liaison setting, we often co-manage patients with a neuropsychiatric disorder that precludes them from participating fully in medical decisions. Other times, patients come to our attention involuntarily (eg, by way of medical admission) having a high level of premorbid autonomy: They make their own life decisions, choose not to engage in psychiatric treatment, administer their funds (when they have them), and so on.

Complex ethical situations can arise when (1) there is disagreement between physician and patient and (2) payment for care or insurance coverage plays a role in disposition plans or long-term placement. Public institutions might have a modus operandi that allows for extra room to deliberate and keep the treatment conversation going—more so than for-profit health centers, where financial forces can sway providers’ judgment toward autonomy, regardless of what is best for the patient.

Summing up: Let’s be Hippocratic psychiatrists

As many forces continue to influence the way we practice the art and science of medicine and psychiatry, it’s important to pay close attention to ongoing challenges and utilize organized medicine to advocate for better ways of running an effective consultation service in an ethical manner. As a trainee and future psychosomatic medicine psychiatrist, I am committed to starting these conversations wherever I go.

We need novel ways to look at, question, understand, study, and review our clinical practice to effectively tackle these challenges as we continue advancing as a field.