Reviews

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

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.

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

The Advisory Committee on Immunization Practices (ACIP) took the unusual step at its June 2016 meeting of recommending against using a currently licensed vaccine, live attenuated influenza vaccine (LAIV), in the 2016-2017 influenza season.¹ ACIP based its recommendation on surveillance data collected by the US Influenza Vaccine Effectiveness Network of the Centers for Disease Control and Prevention (CDC), which showed poor effectiveness by the LAIV vaccine among children and adolescents during the past 3 years.

The US Food and Drug Administration (FDA), however, has chosen not to take any action on this matter, saying on its Web site it “has determined that specific regulatory action is not warranted at this time. This determination is based on FDA’s review of manufacturing and clinical data supporting licensure … the totality of the evidence presented at the ACIP meeting, taking into account the inherent limitations of observational studies conducted to evaluate influenza vaccine effectiveness, as well as the well-known variability of influenza vaccine effectiveness across influenza seasons.”²

The Advisory Committee on Immunization Practices recommends against using the nasal aerosol LAIV vaccine this flu season.

CDC data for the 2015-2016 flu season showed the effectiveness of LAIV to be just 3% among children 2 years through 17 years of age.³ The reason for this apparent lack of effectiveness is unknown. Other LAIV-effectiveness studies conducted in the 2015-2016 season—one each, in the United States, United Kingdom, and Finland—had results that differed from the CDC surveillance data, with effectiveness ranging from 46% to 58% against all strains combined.² These results are comparable to vaccine effectiveness found in observational studies in children for both LAIV and inactivated influenza vaccines (IIV) in prior seasons.²

Vaccine manufacturers had projected that 171 to 176 million doses of flu vaccine, in all forms, would be available in the United States during the 2016-2017 season.³ LAIV accounts for about 8% of the total supply of influenza vaccine in the United States,³ and ACIP’s recommendation is not expected to create shortages of other options for the upcoming season. However, the LAIV accounts for one-third of flu vaccines administered to children, and clinicians who provide vaccinations to children have already ordered their vaccine supplies for the upcoming season. Also, it is not clear if children who have previously received the LAIV product will now accept other options for influenza vaccination—all of which involve an injection.

Whether the recommendation against LAIV will continue after this season is also unknown.

What happened during the 2015-2016 influenza season?

The 2015-2016 influenza season was relatively mild with the peak activity occurring in March, somewhat later than in previous years. The circulating influenza strains matched closely to those in the vaccine, making it more effective than the previous year’s vaccine. The predominant circulating strain was A (H1N1), accounting for 58% of illness; A (H3N2) caused 6% of cases and all B types together accounted for 34%.⁴ The hospitalization rate for all ages was 31.3/100,000 compared with 64.1 the year before.⁵ There were 85 pediatric deaths compared with 148 in 2014-2015.⁶

Vaccine effectiveness among all age groups and against all circulating strains was 47%.⁴ No major vaccine safety concerns were detected. Among those who received IIV3, there was a slight increase in the incidence of Guillain-Barré syndrome of 2.6 cases per one million vaccines.⁷

Other recommendations for 2016-2017

Once again, ACIP recommends influenza vaccine for all individuals 6 months and older.⁸ The CDC additionally specifies particular groups that should not skip vaccination given that they are at high risk of complications from influenza infection or because they could expose high-risk individuals to infection (TABLE 1).⁹

There will continue to be a selection of trivalent and quadrivalent influenza vaccine products in 2016-2017. Trivalent products will contain 3 viral strains: A/California/7/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2) and B/Brisbane/60/2008.¹⁰ The quadrivalent products will contain those 3 antigens plus B/Phuket/3073/2013.¹⁰ The H3N2 strain is different from the one in last year’s vaccine. Each year, influenza experts analyze surveillance data to predict which circulating strains will predominate in North America, and these antigens constitute the vaccine formulation. The accuracy of this prediction in large part determines how effective the vaccine will be that season.

Two new vaccines have been approved for use in the United States. A quadrivalent cell culture inactivated vaccine (CCIV4), Flucelvax, was licensed in May 2016. It is prepared from virus propagated in canine kidney cells, not with an egg-based production process. It is approved for use in individuals 4 years of age and older.⁸ Fluad, an adjuvanted trivalent inactivated influenza vaccine, was licensed in late 2015 for individuals 65 years of age and older.⁸ This is the first adjuvanted influenza vaccine licensed in the United States and will compete with high-dose quadrivalent vaccine for use in older adults. ACIP does not express a preference for any vaccine in this age group.

Two other vaccines should also be available by this fall: Flublok, a quadrivalent recombinant influenza vaccine for individuals 18 years and older, and Flulaval, a quadrivalent inactivated influenza vaccine, for individuals 6 months of age and older. TABLE 2¹¹ lists approved influenza vaccines.

Issues specific to children

Deciding how many vaccine doses children need has been further simplified. Children younger than 9 years need 2 doses if they have received fewer than 2 doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The interval between the 2 doses should be at least 4 weeks. The 2 doses do not have to be the same product; importantly, do not delay a second dose just to obtain the same product used for the first dose. Also, one dose can be trivalent and the other one quadrivalent, although this offers less-than-optimal protection against the B-virus that is only in the quadrivalent product.

Children younger than 9 years require only one dose if they have received 2 or more total doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The 2 previous doses need not have been received during the same influenza season or consecutive influenza seasons.

In children ages 6 through 23 months there is a slight increased risk of febrile seizure if the influenza vaccine is co-administered with other vaccines, specifically pneumococcal conjugate vaccine (PCV 13) and diphtheria-tetanus-acellular-pertussis (DTaP). The 3 vaccines administered at the same time result in 30 febrile seizures per 100,000 children;¹² the rate is lower when influenza vaccine is co-administered with only one of the others. ACIP believes that the risk of a febrile seizure, which does no long-term harm, does not warrant delaying vaccines that could be co-administered.¹³

Egg allergy requires no special precautions

Two new vaccines are available: A quadrivalent cell-culture inactivated vaccine for those ≥4 years and an adjuvanted trivalent inactivated influenza vaccine for those ≥65 years.

Evidence continues to grow that influenza vaccine products do not contain enough egg protein to cause significant problems in those with a history of egg allergies. This year’s recommendations state that no special precautions are needed regarding the anatomic site of immunization or the length of observation after administering influenza vaccine in those with a history of allergies to eggs, no matter how severe. All vaccine-administration facilities should be able to respond to any hypersensitivity reaction, and the standard waiting time for observation after all vaccinations is 15 minutes.

Antiviral medications for treatment or prevention

Most influenza strains circulating in 2016-2017 are expected to remain sensitive to oseltamivir and zanamivir, which can be used for treatment or disease prevention. A third neuraminidase inhibitor, peramivir, is available for intravenous use in adults 18 and older. Treatment is recommended for those who have confirmed or suspected influenza and are at high risk for complications (TABLE 3).¹⁴ Consideration of antiviral chemoprevention is recommended under certain circumstances (TABLE 4).^15,16 The CDC influenza Web site lists recommended doses and duration for each antiviral for treatment and chemoprevention.¹⁵

The Advisory Committee on Immunization Practices (ACIP) took the unusual step at its June 2016 meeting of recommending against using a currently licensed vaccine, live attenuated influenza vaccine (LAIV), in the 2016-2017 influenza season.¹ ACIP based its recommendation on surveillance data collected by the US Influenza Vaccine Effectiveness Network of the Centers for Disease Control and Prevention (CDC), which showed poor effectiveness by the LAIV vaccine among children and adolescents during the past 3 years.

The US Food and Drug Administration (FDA), however, has chosen not to take any action on this matter, saying on its Web site it “has determined that specific regulatory action is not warranted at this time. This determination is based on FDA’s review of manufacturing and clinical data supporting licensure … the totality of the evidence presented at the ACIP meeting, taking into account the inherent limitations of observational studies conducted to evaluate influenza vaccine effectiveness, as well as the well-known variability of influenza vaccine effectiveness across influenza seasons.”²

The Advisory Committee on Immunization Practices recommends against using the nasal aerosol LAIV vaccine this flu season.

CDC data for the 2015-2016 flu season showed the effectiveness of LAIV to be just 3% among children 2 years through 17 years of age.³ The reason for this apparent lack of effectiveness is unknown. Other LAIV-effectiveness studies conducted in the 2015-2016 season—one each, in the United States, United Kingdom, and Finland—had results that differed from the CDC surveillance data, with effectiveness ranging from 46% to 58% against all strains combined.² These results are comparable to vaccine effectiveness found in observational studies in children for both LAIV and inactivated influenza vaccines (IIV) in prior seasons.²

Vaccine manufacturers had projected that 171 to 176 million doses of flu vaccine, in all forms, would be available in the United States during the 2016-2017 season.³ LAIV accounts for about 8% of the total supply of influenza vaccine in the United States,³ and ACIP’s recommendation is not expected to create shortages of other options for the upcoming season. However, the LAIV accounts for one-third of flu vaccines administered to children, and clinicians who provide vaccinations to children have already ordered their vaccine supplies for the upcoming season. Also, it is not clear if children who have previously received the LAIV product will now accept other options for influenza vaccination—all of which involve an injection.

Whether the recommendation against LAIV will continue after this season is also unknown.

What happened during the 2015-2016 influenza season?

The 2015-2016 influenza season was relatively mild with the peak activity occurring in March, somewhat later than in previous years. The circulating influenza strains matched closely to those in the vaccine, making it more effective than the previous year’s vaccine. The predominant circulating strain was A (H1N1), accounting for 58% of illness; A (H3N2) caused 6% of cases and all B types together accounted for 34%.⁴ The hospitalization rate for all ages was 31.3/100,000 compared with 64.1 the year before.⁵ There were 85 pediatric deaths compared with 148 in 2014-2015.⁶

Vaccine effectiveness among all age groups and against all circulating strains was 47%.⁴ No major vaccine safety concerns were detected. Among those who received IIV3, there was a slight increase in the incidence of Guillain-Barré syndrome of 2.6 cases per one million vaccines.⁷

Other recommendations for 2016-2017

Once again, ACIP recommends influenza vaccine for all individuals 6 months and older.⁸ The CDC additionally specifies particular groups that should not skip vaccination given that they are at high risk of complications from influenza infection or because they could expose high-risk individuals to infection (TABLE 1).⁹

There will continue to be a selection of trivalent and quadrivalent influenza vaccine products in 2016-2017. Trivalent products will contain 3 viral strains: A/California/7/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2) and B/Brisbane/60/2008.¹⁰ The quadrivalent products will contain those 3 antigens plus B/Phuket/3073/2013.¹⁰ The H3N2 strain is different from the one in last year’s vaccine. Each year, influenza experts analyze surveillance data to predict which circulating strains will predominate in North America, and these antigens constitute the vaccine formulation. The accuracy of this prediction in large part determines how effective the vaccine will be that season.

Two new vaccines have been approved for use in the United States. A quadrivalent cell culture inactivated vaccine (CCIV4), Flucelvax, was licensed in May 2016. It is prepared from virus propagated in canine kidney cells, not with an egg-based production process. It is approved for use in individuals 4 years of age and older.⁸ Fluad, an adjuvanted trivalent inactivated influenza vaccine, was licensed in late 2015 for individuals 65 years of age and older.⁸ This is the first adjuvanted influenza vaccine licensed in the United States and will compete with high-dose quadrivalent vaccine for use in older adults. ACIP does not express a preference for any vaccine in this age group.

Two other vaccines should also be available by this fall: Flublok, a quadrivalent recombinant influenza vaccine for individuals 18 years and older, and Flulaval, a quadrivalent inactivated influenza vaccine, for individuals 6 months of age and older. TABLE 2¹¹ lists approved influenza vaccines.

Issues specific to children

Deciding how many vaccine doses children need has been further simplified. Children younger than 9 years need 2 doses if they have received fewer than 2 doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The interval between the 2 doses should be at least 4 weeks. The 2 doses do not have to be the same product; importantly, do not delay a second dose just to obtain the same product used for the first dose. Also, one dose can be trivalent and the other one quadrivalent, although this offers less-than-optimal protection against the B-virus that is only in the quadrivalent product.

Children younger than 9 years require only one dose if they have received 2 or more total doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The 2 previous doses need not have been received during the same influenza season or consecutive influenza seasons.

In children ages 6 through 23 months there is a slight increased risk of febrile seizure if the influenza vaccine is co-administered with other vaccines, specifically pneumococcal conjugate vaccine (PCV 13) and diphtheria-tetanus-acellular-pertussis (DTaP). The 3 vaccines administered at the same time result in 30 febrile seizures per 100,000 children;¹² the rate is lower when influenza vaccine is co-administered with only one of the others. ACIP believes that the risk of a febrile seizure, which does no long-term harm, does not warrant delaying vaccines that could be co-administered.¹³

Egg allergy requires no special precautions

Two new vaccines are available: A quadrivalent cell-culture inactivated vaccine for those ≥4 years and an adjuvanted trivalent inactivated influenza vaccine for those ≥65 years.

Evidence continues to grow that influenza vaccine products do not contain enough egg protein to cause significant problems in those with a history of egg allergies. This year’s recommendations state that no special precautions are needed regarding the anatomic site of immunization or the length of observation after administering influenza vaccine in those with a history of allergies to eggs, no matter how severe. All vaccine-administration facilities should be able to respond to any hypersensitivity reaction, and the standard waiting time for observation after all vaccinations is 15 minutes.

Antiviral medications for treatment or prevention

Most influenza strains circulating in 2016-2017 are expected to remain sensitive to oseltamivir and zanamivir, which can be used for treatment or disease prevention. A third neuraminidase inhibitor, peramivir, is available for intravenous use in adults 18 and older. Treatment is recommended for those who have confirmed or suspected influenza and are at high risk for complications (TABLE 3).¹⁴ Consideration of antiviral chemoprevention is recommended under certain circumstances (TABLE 4).^15,16 The CDC influenza Web site lists recommended doses and duration for each antiviral for treatment and chemoprevention.¹⁵

The Advisory Committee on Immunization Practices (ACIP) took the unusual step at its June 2016 meeting of recommending against using a currently licensed vaccine, live attenuated influenza vaccine (LAIV), in the 2016-2017 influenza season.¹ ACIP based its recommendation on surveillance data collected by the US Influenza Vaccine Effectiveness Network of the Centers for Disease Control and Prevention (CDC), which showed poor effectiveness by the LAIV vaccine among children and adolescents during the past 3 years.

The US Food and Drug Administration (FDA), however, has chosen not to take any action on this matter, saying on its Web site it “has determined that specific regulatory action is not warranted at this time. This determination is based on FDA’s review of manufacturing and clinical data supporting licensure … the totality of the evidence presented at the ACIP meeting, taking into account the inherent limitations of observational studies conducted to evaluate influenza vaccine effectiveness, as well as the well-known variability of influenza vaccine effectiveness across influenza seasons.”²

The Advisory Committee on Immunization Practices recommends against using the nasal aerosol LAIV vaccine this flu season.

CDC data for the 2015-2016 flu season showed the effectiveness of LAIV to be just 3% among children 2 years through 17 years of age.³ The reason for this apparent lack of effectiveness is unknown. Other LAIV-effectiveness studies conducted in the 2015-2016 season—one each, in the United States, United Kingdom, and Finland—had results that differed from the CDC surveillance data, with effectiveness ranging from 46% to 58% against all strains combined.² These results are comparable to vaccine effectiveness found in observational studies in children for both LAIV and inactivated influenza vaccines (IIV) in prior seasons.²

Vaccine manufacturers had projected that 171 to 176 million doses of flu vaccine, in all forms, would be available in the United States during the 2016-2017 season.³ LAIV accounts for about 8% of the total supply of influenza vaccine in the United States,³ and ACIP’s recommendation is not expected to create shortages of other options for the upcoming season. However, the LAIV accounts for one-third of flu vaccines administered to children, and clinicians who provide vaccinations to children have already ordered their vaccine supplies for the upcoming season. Also, it is not clear if children who have previously received the LAIV product will now accept other options for influenza vaccination—all of which involve an injection.

Whether the recommendation against LAIV will continue after this season is also unknown.

What happened during the 2015-2016 influenza season?

The 2015-2016 influenza season was relatively mild with the peak activity occurring in March, somewhat later than in previous years. The circulating influenza strains matched closely to those in the vaccine, making it more effective than the previous year’s vaccine. The predominant circulating strain was A (H1N1), accounting for 58% of illness; A (H3N2) caused 6% of cases and all B types together accounted for 34%.⁴ The hospitalization rate for all ages was 31.3/100,000 compared with 64.1 the year before.⁵ There were 85 pediatric deaths compared with 148 in 2014-2015.⁶

Vaccine effectiveness among all age groups and against all circulating strains was 47%.⁴ No major vaccine safety concerns were detected. Among those who received IIV3, there was a slight increase in the incidence of Guillain-Barré syndrome of 2.6 cases per one million vaccines.⁷

Other recommendations for 2016-2017

Once again, ACIP recommends influenza vaccine for all individuals 6 months and older.⁸ The CDC additionally specifies particular groups that should not skip vaccination given that they are at high risk of complications from influenza infection or because they could expose high-risk individuals to infection (TABLE 1).⁹

There will continue to be a selection of trivalent and quadrivalent influenza vaccine products in 2016-2017. Trivalent products will contain 3 viral strains: A/California/7/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2) and B/Brisbane/60/2008.¹⁰ The quadrivalent products will contain those 3 antigens plus B/Phuket/3073/2013.¹⁰ The H3N2 strain is different from the one in last year’s vaccine. Each year, influenza experts analyze surveillance data to predict which circulating strains will predominate in North America, and these antigens constitute the vaccine formulation. The accuracy of this prediction in large part determines how effective the vaccine will be that season.

Two new vaccines have been approved for use in the United States. A quadrivalent cell culture inactivated vaccine (CCIV4), Flucelvax, was licensed in May 2016. It is prepared from virus propagated in canine kidney cells, not with an egg-based production process. It is approved for use in individuals 4 years of age and older.⁸ Fluad, an adjuvanted trivalent inactivated influenza vaccine, was licensed in late 2015 for individuals 65 years of age and older.⁸ This is the first adjuvanted influenza vaccine licensed in the United States and will compete with high-dose quadrivalent vaccine for use in older adults. ACIP does not express a preference for any vaccine in this age group.

Two other vaccines should also be available by this fall: Flublok, a quadrivalent recombinant influenza vaccine for individuals 18 years and older, and Flulaval, a quadrivalent inactivated influenza vaccine, for individuals 6 months of age and older. TABLE 2¹¹ lists approved influenza vaccines.

Issues specific to children

Deciding how many vaccine doses children need has been further simplified. Children younger than 9 years need 2 doses if they have received fewer than 2 doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The interval between the 2 doses should be at least 4 weeks. The 2 doses do not have to be the same product; importantly, do not delay a second dose just to obtain the same product used for the first dose. Also, one dose can be trivalent and the other one quadrivalent, although this offers less-than-optimal protection against the B-virus that is only in the quadrivalent product.

Children younger than 9 years require only one dose if they have received 2 or more total doses of trivalent or quadrivalent influenza vaccine before July 1, 2016. The 2 previous doses need not have been received during the same influenza season or consecutive influenza seasons.

In children ages 6 through 23 months there is a slight increased risk of febrile seizure if the influenza vaccine is co-administered with other vaccines, specifically pneumococcal conjugate vaccine (PCV 13) and diphtheria-tetanus-acellular-pertussis (DTaP). The 3 vaccines administered at the same time result in 30 febrile seizures per 100,000 children;¹² the rate is lower when influenza vaccine is co-administered with only one of the others. ACIP believes that the risk of a febrile seizure, which does no long-term harm, does not warrant delaying vaccines that could be co-administered.¹³

Egg allergy requires no special precautions

Two new vaccines are available: A quadrivalent cell-culture inactivated vaccine for those ≥4 years and an adjuvanted trivalent inactivated influenza vaccine for those ≥65 years.

Evidence continues to grow that influenza vaccine products do not contain enough egg protein to cause significant problems in those with a history of egg allergies. This year’s recommendations state that no special precautions are needed regarding the anatomic site of immunization or the length of observation after administering influenza vaccine in those with a history of allergies to eggs, no matter how severe. All vaccine-administration facilities should be able to respond to any hypersensitivity reaction, and the standard waiting time for observation after all vaccinations is 15 minutes.

Antiviral medications for treatment or prevention

Most influenza strains circulating in 2016-2017 are expected to remain sensitive to oseltamivir and zanamivir, which can be used for treatment or disease prevention. A third neuraminidase inhibitor, peramivir, is available for intravenous use in adults 18 and older. Treatment is recommended for those who have confirmed or suspected influenza and are at high risk for complications (TABLE 3).¹⁴ Consideration of antiviral chemoprevention is recommended under certain circumstances (TABLE 4).^15,16 The CDC influenza Web site lists recommended doses and duration for each antiviral for treatment and chemoprevention.¹⁵

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

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.