Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Division of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


Criteria for Alzheimer’s disease and preclinical dementia have been proposed recently, which include potential biomarkers of the illness. Nonetheless, the etiology of the illness remains uncertain despite consistent associations described for cerebral amyloid and hyperphosphorylated tau pathologies. As a result, further progress toward understanding age-related changes in cognition that are not related to dementia is critical both to characterize healthy aging but also to develop interventions that will sustain cognitive performance. This will be the case even if proposed biomarkers become powerful predictors of the presence of disease.


Preliminary criteria for diagnosis of Alzheimer’s disease in both its clinical and pre-clinical forms have appeared in the proposed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,1,2 and subsequently by work groups convened by the National Institute on Aging and the Alzheimer’s Association.3-5 Both suggest that bio-markers related to amyloid or the microtubule protein tau soon may be incorporated into the diagnostic process. The appeal of putative biomarkers of dementia is their promise of signaling the presence of a disease process before cognition or brain topography become noticeably impaired. In addition to anteceding the onset of symptoms, biomarkers might be less subject to variations seen in healthy cognitive performance related to education, vocation, or innate intelligence. The proponents of biomarker research assume that amyloid is the signal event in Alzheimer’s disease. Amyloid and hyperphosporylated tau are pathology consistently associated with Alzheimer’s disease. But how distal are these pathologies from the pathoetiology of the illness?

Uncertainty about the primary pathophysiology of Alzheimer’s disease has raised skepticism about the use of biomarkers.6 Yet, interventions applied once synaptic atrophy and neuronal death are manifest as cognitive impairment may be too late to be effective. Further, intervention trials to test the amyloid hypothesis among patients selected on the basis of these preliminary criteria could take a decade to complete. Even if the spread of amlyoid in the brain can be reduced or reversed, the demonstration of preserved or improved cognition will be required to establish efficacy. As a result, attention to progress in the characterization age-related changes in cognition is critical to refining criteria for preclinical dementia. The study of working memory and executive function now underway in the Research Domain Criteria initiative of the National Institute of Mental Health7,8 may further advance the assessment of cognitive processes and neural circuits sensitive to the earliest signs of Alzheimer’s disease.

Cognitive Constructs and Aging

Cognitive constructs refer to mental processes which have both scientific and clinical utility yet are approximations of reality based on observation and theory. Functional imaging has revealed age-related changes relevant to the theoretical constructs, but no unified phenomenon which might represent a simple theory of aged cognition has emerged. Nonetheless, awareness of these constructs and how they are changed for better or worse with age will have clinical implications when genuinely therapeutic agents arrive for the treatment of dementia. Prominent constructs recently reviewed by Reuter-Lorenz and Park9 appear in bold followed by descriptions.

Working memory, that component of the cognitive system which retains information for immediate use, is an area of intense interest for clinicians caring with older adults but for neuroscientists as well. Memory screening tests most often rely on working memory by requiring the patient to register, retain (learn), and recall (remember) new information such as a recited list of words or set of image presentations. Older adults perform as well as younger provided the memory load does not exceed four items or require marked executive function to inhibit, reorder, or refresh the list. Thus, when older adults are asked to select from the assortment of recently learned memories or to alternate categories of items, working memory becomes fatigued. Unlike consolidated memory, which seems to have infinite shelf space, working memory is volume dependent and vulnerable to overload. As the memory load increases, both younger and older adults recruit prefrontal cortical areas to manage the load. Older adults reach overload sooner and show a drop in prefrontal activation, suggesting the system has met its limit.

Inhibitory control deficits appear when older adults are given memory tasks in which distractors are also presented. In comparison to a younger adult, the older person is less likely to ignore, screen out, or delete irrelevant stimuli. When instructed to remember a sequence of words or images followed by items to be ignored, older adults show greater brain activation for the latter than do younger adults. When instructed to generate a list of words starting with the letter “S” followed by an instruction to list words starting with the letter “A,” older adults are more likely to insert S-words into the A-word list. Thus, age-related inhibitory dysfunction mediated by prefrontal processes results in impairments in the initial stage of information processing, placing further limits on working memory capacity and efficiency.

Processing speed decrements are the most widely accepted explanation for decline in cognitive processes during late life. Changes in white matter structure and integrity are largely responsible. It is as though age and cardiovascular illness fray the insulation in neural circuits. However, the effects are not uniform. Some neural circuits and the cognitive processes they serve may be more intact and more capable of compensating for those with less integrity. As a result, slowed processing speed is not considered a sufficient explanation for cognitive decline during aging.

Long-term memory deficits have been ascribed to a number of age-related changes in brain structure and cognitive function. Older adults are less effective at encoding new information for memory tests. However, when given contextual or categorical cues associated with the memory item, their performance improves. Such tests of episodic memory are also sensitive to loss of volume and under-activation of the hippocampus and parahippocampus, two areas affected early in Alzheimer’s disease. Implicit, automatic, or procedural memory functions out of awareness and is related to previously learned material that can be applied to current tasks with little conscious effort. This form of effortless recall, particularly when associated with semantic processing, involves left inferior prefrontal regions and is relatively preserved in older people.

Constructs from Imaging Studies of Brain Regions and Neural Circuitry

Functional imaging studies with positron emission tomography or functional magnetic resonance imaging scans have provided a number of discoveries about regional differences in the aging brain. For example, compared to younger people, older adults will activate a greater number of brain regions to meet the same cognitive challenge. Hemispheric dominance, whether for verbal processing on the left or spatial processing on the right, is diminished such that functional asymmetry and localization are reduced. Over-activation is also seen in both posterior and anterior regions of cortex accompanied by a general posterior to anterior shift in activation. The phenomenon is thought not to be a result simply of cerebrovascular aging. Over-activation may be associated with superior cognitive performance and represent compensatory enhancement of neural circuitry. However compensation has its price.

The medial prefrontal, medial, and lateral parietal brain areas are known as the default network. These regions are highly interconnected, more active at rest than during purposeful activity, and associated with internal rather than external stimuli. The default network manages ongoing attention to the environment, self-focus, and reflective memories. However, with advancing age, the network loses interconnectivity and over-reacts to external stimuli. As a result, frontal areas are recruited to compensate, causing loss of efficiency and accuracy.

De-differentiation is the result of lost topographic specificity and decline in neural plasticity. Additional regions of cortex have to be recruited, not to reach a new equilibrium, but rather to respond to loss of specialization. For example, face recognition is specific to the ventral visual cortex, but as this area loses functionality with age, prefrontal areas are recruited to manage the work load placed on working memory. There is a general posterior to anterior activation in the cortex with the medial, lateral, and anterior prefrontal cortex being over-activated to compensate for under-activation in the medial temporal lobe and ventral visual cortex.

Frontal over-activation makes older adults vulnerable to age- and illness-related prefrontal deficits. In addition, there is an increased noise to signal ratio. As dopamine levels decline with age, the strength of synaptic signaling falls while the background neural noise does not.

Older adults are also more likely to exhibit difficulties with proactive versus reactive cognitive control. Because of changes in executive function and prefrontal structures, older adults are less able to benefit from cues and context that might precede a sequence of stimuli. Rather, they rely more than younger people on cognitive procedures that occur during stimulus presentation. This reduces processing speed as well as the stimulus load that can be successfully processed. Thus, their executive function is more reactive than proactive or anticipatory. They multi-task with difficulty.

From “CRUNCH” to “STAC”

How, then, do we explain the increasing proportion of older adults who maintain sufficient cognitive function to remain independent into late life?”10 Reuter-Lorenz and Park9 present two hypothetical mechanisms to account for the maintenance of cognitive performance in late life, shown in the Figure. The Compensation-Related Utilization of Neural Circuits hypothesis suggests that cognitive processes become rerouted to new or additional circuits as age and illness wear the brain down. As one area of mental hardware deteriorates, another is recruited to take its place. A virtual scaffold gradually emerges and is made possible by the distribution of cognitive processes to frontal and other areas, including both hemispheres, and to new neurons via neurogenesis. The Scaffolding Theory of Aging and Cognition adds the notion that the brain’s software may be enhanced at the same time that the circuitry is being upgraded. The scaffold is enhanced by learning, physical exercise, cognitive stimulation, and social engagement. The impact on cognitive performance will vary as a result of both the quality of the structure of the scaffold and personal behavior. In this way, not only do age and illness affect cognition, but so do personal history, ongoing mental activity, and the environment.




Advances in cognitive neuroscience buttressed by interest in dementia biomarkers and functional imaging techniques promise to increase the measurement of risk for the development of Alzheimer’s disease. However, equally important are insights into compensatory mechanisms and the plasticity of neural circuitry that may argue for interventions which might sustain if not improve cognitive performance to the end of the life span.11 This will be particularly important when treatments emerge to modify the disease process and slow the rate of decline among people with dementia. An understanding of how biomarkers might predict dementia will not obviate the need to advance our understanding of aging and cognition in healthy active older adults. PP


1. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association. In press.
2. Kennedy GJ. Proposed revisions for the diagnostic categories of dementia in the DSM-5. Primary Psychiatry. 2010;17(5):26-28.
3. Alz.org. Proposed criteria for Alzheimer’s disease dementia. Available at: www.alz.org/research/diagnostic_criteria/dementia_recommendations.pdf. Accessed August 10, 2010.
4. Alz.org. Proposed criteria for mild cognitive impairment due to Alzheimer’s disease. Available at: www.alz.org/research/diagnostic_criteria/mci_reccomendations.pdf. Accessed August 10, 2010.
5. Alz.org. Proposed criteria for preclinical Alzheimer’s disease. Available at: www.alz.org/research/diagnostic_criteria/preclinical_recommendations.pdf. Accessed August 10, 2010.
6. Kolata G. In Alzheimer’s research, hope for prevention. The New York Times. August 5, 2010: A18.
7. Insel T, Cuthbert B, Garvey M, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748-751.
8. NIMH Research Domain Criteria (RDoC). Available at: www.nimh.nih.gov/research-funding/nimh-research-domain-criteria-rdoc.shtml. Accessed August 12, 2010.
9. Reuter-Lorenz PA, Park DC. Human neuroscience and the aging mind: a new look at old problems. Journal of Gerontology: Psychological Sciences. 2010;65B(4):405-415.
10. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135.
11. Rae MJ, Butler RN, Campisi J, et al. The demographic and biomedical case for late-life interventions in aging. Sci Transl Med. 2010;2(40):40cm21.



This interview took place on June 10, 2010 and was conducted by Norman Sussman, MD.

Disclosure: Dr. Holt reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

If you would like to access this interview online, please visit www.primarypsychiatry.com.

Are we at a point where neuroimaging or neural biomarkers of psychiatric illness can help us identify and even start treating diseases early in their development?

One central goal in neuroimaging research in psychiatric illness is to define the neural correlates of particular psychiatric illnesses so that they can be used as biomarkers of the illness. The basic assumption is that at least some of the brain abnormalities found in people with an illness should also be seen in people who are at risk for that illness but not yet ill. These neural abnormalities could be used as biomarkers of risk; they could work just like stress tests, Papanicolaou smears, or other methods used for early risk detection by other fields of medicine. Then, these biomarkers would allow us to treat people at risk in a targeted, cost-effective way with preventive interventions.

Neuroimaging research in psychiatry is still a relatively young field. It started in the mid-1970s, with the development of computerised tomography scan. The high-resolution magnetic resonance imaging (MRI)-based methods that we use now have only been used since the mid- to late-90s. We have only been conducting this kind of research for the past 10–15 years. The spatial and temporal resolution of these methods are still improving. We have come a long way in identifying neural correlates of psychiatric illness, but we still have a way to go.

Does evaluating multiple aspects of illness in addition to neuroimaging provide a better prediction tool?

Yes. The key may be to use multiple methods in combination to develop a risk signature of psychiatric illnesses. However, it is challenging because a lot of the neural correlates of illness turn out to be somewhat nonspecific. They often overlap with what is seen in healthy people. Also, the different illnesses can show similar abnormalities. This may say more about our diagnostic and classification systems than the biology of the illnesses we study.

There has been a recent set of breakthroughs that will help push forward this line of research. There have been recent studies showing that certain treatments, like cognitive-behavioral therapy1,2 and fish oil,3 may actually prevent the development of certain major mental illnesses, such as schizophrenia and depression.

Can neural dysfunction predict who in combat might experience posttraumatic stress disorder (PTSD)?

PTSD has been associated with a set of abnormalities in brain function, including impaired function of the medial prefrontal cortex (PFC), exaggerated amygdala responses, and dysfunctional connections between the medial PFC and the amygdala. Risk for PTSD has been studied extensively by a group at Massachusetts General Hospital in Boston led by Roger K. Pitman, MD, using various neuroimaging methods including functional MRI (fMRI) as well as psychophysiologic techniques.4,5 They have measured skin conductance responses in response to emotional stimuli and during fear conditioning. They have used these methods to study brain function of combat veterans who do or do not have PTSD. The elegant aspect of their design is that each of the combat veterans they have studied also has an identical twin brother who has not been exposed to combat. The idea is that any abnormalities they find in the veterans with PTSD that they also find in those veterans’ twin brothers could be related to risk for PTSD.

They found several abnormalities in the veterans with PTSD and their twins, such as elevated dorsal anterior cingulate gyrus activity and an enlargement of a space in the middle of the brain called the cavum septum pellucidum. Now that they have found these abnormalities that could be related to risk, they can examine them prospectively in soldiers before they go into combat, to see if these actually are risk markers for PTSD.

Is it true that when patients with neuronal loss in areas like the hippocampus are effectively treated with an antidepressant, neuronal sprouting occurs because of an increase in brain-derived neurotropic factor?

The rat model of the effects of stress on the hippocampus differs from what we see in humans to some extent. Still, there is a lot of evidence for the effects of neurotrophic factors on brain regions affected in psychiatric illness and that antidepressants increase the release of these factors and possibly affect medial temporal lobe volume and neurogenesis. This is an active area of study right now, in research dedicated to developing novel treatments for depression and schizophrenia.

Addictive disorders are common. What do we know about reward circuitry responses?

There has been much research on the reward system of the brain, both in rats and monkeys as well as in humans. Research in humans has mostly been conducted using fMRI and positron emission tomography. There is a network of regions which includes the ventral striatum, orbital frontal cortex, dorsal lateral PFC, and dopaminergic cell groups of the midbrain, which are involved in the pursuit of reward and the experience, and anticipation of rewarding stimuli—all aspects of reward-related responses.

Addiction, major depressive disorder, and schizophrenia have each been associated with a different type of abnormality in the circuitry. For example, addiction may be most related to an impairment in what we call “top-down control” by the PFC of the function of subcortical reward circuitry. Schizophrenia, particularly the negative symptoms of the disorder,  may be related to an impairment in the anticipation, or memory, of rewarding experiences, which may have a slightly different mechanism. We are still in the process of understanding what the specific neural correlates are of these behavioral abnormalities associated with the reward system. Luckily, this system has been very well-characterized in animal models.

If it really turns out to be the case that addiction is associated with a reduction in the top-down control of reward-related responses, there may be a way to augment the activity of the PFC and its modulation of subcortical activity in the striatum and other centers that may be dysregulated in these patients.

Have you done any work on understanding delusions of schizophrenia from a neural point of view?

Yes. Our model comes from several lines of converging evidence that suggest that delusions result from an abnormality in emotional learning and memory.

The idea is that we have a somewhat flexible neural system that tells us whether something in the environment is important, dangerous, or relevant to us in some way. It actually appears that we have two interacting systems that evaluate the emotional meaning of information in the environment. There is a fast, sometimes inaccurate system, and then a slow but more detail-oriented and precise system. Sometimes the fast system misfires, even in healthy non-delusional people. Then, the second more accurate system kicks in to correct these errors.

When people develop delusional ideas, the system misfires frequently, telling the person that something in his or her environment is important, relevant, or dangerous. Yet, there is no mechanism that comes in to correct these misperceptions.

Our lab, among others, has found neuroimaging evidence to support this hypothesis. We have found that delusions are associated with misfiring of certain regions of the brain, such as the cingulate gyrus, in response to information that is not personally relevant or emotionally significant for most people.6-8

Is there a correlation between treatment, elimination of delusions, and changes in these areas?

Neuroimaging studies that conduct this type of within-subject comparison represent the best approach to testing this model of delusions, but it is difficult to do this kind of study well. If you are not careful, there will be several things that are changing at the same time, like doses of medication and symptom severity. We are conducting a study like this right now to see if we can tease out the effects of treatment on delusions and the associated changes in brain function.

Is quantitative electroencephalogram (EEG) valuable in your work?

I have done some event-related potential (ERP) work and I think it is extremely valuable. It can be a very good companion to fMRI because it has very good temporal resolution. However, the spatial resolution is not very good, while fMRI has the opposite set of strengths.

fMRI essentially measures blood flow by taking advantage of the fact that the  deoxygenated hemoglobin (deoxyhemoglobin) is paramagnetic. Because deoxyhemoglobin is paramagnetic, we can measure where it is going in the brain because it disrupts the MRI signal in a predictable way.

EEG measures electrical activity of pyramidal neurons. Because it is directly measuring neuronal activity, the electrical discharge of neurons, it is very accurate temporally, on the order of milliseconds. However, because it can only measure activity that is near the surface of the scalp, it can only measure activity of neurons that are near the cortical surface; it cannot provide the sort of spatial resolution that we have with MRI-based methods.

Has there been work on the circuits involved with anxiety disorders?

This brings up a current question in psychiatric neuroimaging research that many are grappling with, which is whether to continue to use the Diagnostic and Statistical Manual of Mental Disorders classification schemes in our research, since these classifications may not reflect unique biologic or neurophysiologic characteristics. For example, social anxiety disorder may be difficult to distinguish neurophysiologically from generalized anxiety disorder or other types of phobias.

Obsessive-compulsive disorder (OCD), however, appears to have a neural signature that is somewhat distinct in comparison to other anxiety disorders. It seems to be associated with more prominent orbital frontal-striatal abnormalities. This is interesting because it is consistent with the impression of many clinicians, that the clinical features of OCD are somewhat distinct from the clinical features of other anxiety disorders. This is in the line with the general idea that the DSM-IV-TR may have it right in some cases but not in others.

What is the major message for our clinical audience at this point?

I believe that we are slowly moving closer to being able to use neuroimaging as a clinical tool to identify people at risk and to measure effects of treatment. A large benefit of neuroimaging research that we have already seen clinically is that it has contributed to the reduction of the stigma associated with psychiatric disorders. It is really helpful for patients to understand that we have identified abnormalities of the brain associated with these disorders. These are medical disorders, which you can see evidence of, in research studies, on an MRI scan.

Have there been any major findings related to the PFC?

The frontal lobe is the part of the cerebral cortex that is most relevant for psychiatric illness. It is the control center of the brain. The dorsal and lateral PFC are involved in decision-making, planning, and task switching—any process that involves conscious choice. The medial and ventral portions of the PFC are involved in emotional perception, introspective activity, and integrating internal states with incoming sensory information. Many psychiatric disorders appear to be associated with abnormalities of the PFC, including schizophrenia, bipolar disorder, major depression, and PTSD.

Are there other brain areas of interest that you would like to comment on?

Neuroimaging researchers are very interested currently in understanding what the midline cortical network does and whether there are abnormalities in the functioning of this network in psychiatric disorders. This network includes the medial PFC and posterior cingulate gyrus. These regions show elevated activity during what people call “stimulus-independent thought,” which you have during times when you are not really engaged in thinking about anything going on in your surrounding environment. Instead, you may be daydreaming or thinking about the past or future. This network is of interest to psychiatric researchers because certain psychiatric disorders are associated with abnormal introspective thinking—either too much or too little of it. So far, it has been shown that this network functions abnormally in schizophrenia and depression.

What have we learned from the research on the neuropsychology of epilepsy?

It is interesting that medial temporal lobe epilepsy is sometimes associated with psychotic symptoms. Abnormalities in the medial temporal lobe are likely involved in the psychosis associated with schizophrenia too.9 A lot of evidence now supports this possibility. There has been some recent evidence showing abnormally elevated activity in a part of the hippocampus, which is within the medial temporal lobe, in people who have schizophrenia, as well as in people who are at risk for schizophrenia and later develop it.10

Epilepsy is an interesting model in that in some cases it has a very specific neuroanatomical correlate associated with psychiatric symptoms. It suggests that we are on the right track and that, at some point, we will understand psychiatric illnesses just as well as neurologists understand epilepsy. PP


1.    Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.
2.    Garber J, Clarke GN, Weersing VR, et al. Prevention of depression in at-risk adolescents: a randomized controlled trial. JAMA. 2009;301(21):2215-2224.
3.    Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.
4.    Pitman RK, Gilbertson MW, Gurvits TV, et al. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Ann N Y Acad Sci. 2006;1071:242-254.
5.    Shin LM, Lasko NB, Macklin ML, et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry. 2009;66(10):1099-1107.
6.    Holt DJ, Titone D, Long LS, et al. The misattribution of salience in delusional patients with schizophrenia. Schizophr Res. 2006;83(2-3):247-256.
7.    Holt DJ, Lebron-Milad K, Milad MR, et al. Extinction memory is impaired in schizophrenia. Biol Psychiatry. 2009;65(6):455-463.
8.    Holt DJ, Lakshmanan B, Freudenreich O, Goff DC, Rauch SL, Kuperberg GR. Dysfunction of a cortical midline network during emotional appraisals in schizophrenia. Schizophr Bull. In press.
9.    Holt DJ, Phillips ML. The human amygdala in schizophrenia. In: Phelps EA, Whalen PJ, eds. The Human Amygdala. New York, NY: Guilford; 2009:344-361.
10.    Schobel SA, Lewandowski NM, Corcoran CM, et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry. 2009;66(9):938-946.


Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.



Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, such as multiple sclerosis; other psychiatric symptoms as a manifestation or complication of neurologic disease; and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease, ie, conversion disorder or somatization disorder. In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In a previous column in Primary Psychiatry, psychiatric issues in stroke were reviewed.3 In this issue, psychiatric issues related to Parkinson’s disease and multiple sclerosis are reviewed.


Parkinson’s Disease

Parkinson’s disease is an idiopathic degenerative disorder characterized by tremor, rigidity, and bradykinesia. Its estimated prevalence is 10–20 cases per 100,000 and its incidence increases with age. While it is thought of as primarily a disease of the elderly, Parkinson’s disease occurs even in adolescents, albeit rarely. Resting tremor (especially “pill-rolling” tremor) is the most obvious feature of Parkinson’s disease and is found in 75% of patients. However, bradykinesia is the most common initial sign, with insidious onset, and is therefore easily misdiagnosed as depression or apathy; bradykinesia is ultimately the most disabling feature. “Cogwheeling” is the result of tremor superimposed on rigidity. Postural instability due to rigidity as Parkinson’s disease progresses results in increased risk for falls. Abnormal involuntary movements are a result both of Parkinson’s disease and of dopaminergic therapy. Freezing of movement is particularly distressing to patients. In addition to the classic motor symptoms, other common manifestations of Parkinson’s disease include autonomic dysfunction (particularly orthostatic hypotension, bladder and gastrointestinal dysfunction), cognitive dysfunction, depression, and other psychiatric symptoms.



Parkinson’s disease is accompanied by dementia in a substantial minority of cases, and the boundary between Parkinson’s disease with dementia (PD-D) and dementia with Lewy bodies (DLB) is not a clear one. Psychotic symptoms (hallucinations and delusions) occur in 50% to 75% of patients with DLB, 30% to 50% with PD-D, and 5% to 15% of patients with Parkinson’s disease without dementia.1 Hallucinations are usually visual and delusions are most often paranoid. While limited psychotic symptoms with retained insight in Parkinson’s disease have been regarded as benign, a recent study suggests this is not the case and that most individuals’ psychotic symptoms progress over a period of years.4

In the early days of L-dopa treatment, adverse psychiatric reactions, particularly psychotic symptoms, were frequent after initiation of therapy and reported in up to 50% of patients after several years of treatment.1 The addition of carbidopa to L-dopa made this much less common. Psychotic symptoms have been reported as adverse reactions to other dopaminergic drugs in Parkinson’s disease, including bromocriptine, pramipexole, and ropinirole, but have not been clearly related to dose or length of exposure. Anticholinergic drugs are beneficial for Parkinsonian symptoms but pose the risk of aggravating cognitive dysfunction if dementia is also present. Anticholinerigc drugs also may cause psychotic symptoms as part of delirium, whereas the hallucinations and delusions induced by dopaminergic drugs are usually isolated psychotic symptoms unaccompanied by delirium.

Typical neuroleptics, especially high-potency ones, are contraindicated in Parkinson’s disease because they exacerbate symptoms and block the effect of dopaminergic drugs. Clozapine is the only antipsychotic shown in a randomized controlled trial (that also included olanzapine and risperidone) to be effective against psychosis, without aggravation of Parkinson’s disease.5 Quetiapine appeared beneficial for psychotic symptoms without worsening Parkinson’s disease in an open trial,6 but two small randomized controlled trials were negative. Despite its mixed dopamine agonist-antagonist profile, open trials of aripiprazole have not supported its use for psychosis in Parkinson’s disease.7 While there are case reports of psychotic symptoms responding to cholinesterase inhibitors in patients who have PD-D, without aggravating Parkinson’s disease,8 others have reported they caused significant worsening of Parkinson’s disease motor symptoms (which is not surprising since anticholinergic drugs reduce Parkinson’s disease motor symptoms).



Depression is very common in Parkinson’s disease, with a prevalence of up to 40% to 50%.1 Depression may antedate the development of motor symptoms in Parkinson’s disease and is associated with cognitive dysfunction.9,10 Depression and other psychological factors interact to affect the course and outcome of Parkinson’s disease, with depression resulting in impairment of functional capacity and quality of life, but not motor function in Parkinson’s disease.9 It is not known to what extent depression results from brain pathology as opposed the psychological consequences of the progressive disabling nature of Parkinson’s disease. Early in the course of unrecognized Parkinson’s disease, depression may be misdiagnosed because of the patient’s lack of facial expression and motor slowing. Later in Parkinson’s disease, the diagnosis of depression may be missed when fatigue, psychomotor slowing, impaired attention, poor sleep, and sexual dysfunction—all of which can be caused by Parkinson’s disease—are attributed to Parkinson’s disease. The presence of psychological symptoms of depression (eg, dysphoric mood, anhedonia, negativism, guilt) that are out of proportion to the degree of disability in Parkinson’s disease, and of course suicidal ideation, support the diagnosis of major depressive disorder (MDD).11 Mood lability (both unipolar and bipolar) has been described during the late-stage fluctuations known as on-off phenomena that occur after years of L-dopa therapy.1

For treatment of depression in Parkinson’s disease, tricyclic antidepressants (TCAs) may have the side benefit of reducing Parkinson’s disease motor symptoms because of their anticholinergic effects, but this must be balanced against the risk of their aggravating cognitive or autonomic dysfunction. Selective serotonin reuptake inhibitors (SSRIs) have occasionally been reported to exacerbate Parkinson’s disease motor symptoms and rarely have caused extrapyramidal side effects in patients without Parkinson’s disease. Mirtazapine may be a good choice for depression in Parkinson’s disease and may even reduce symptoms of Parkinson’s disease.12 Finally, dopamine agonists like pramipexole may be an alternative to antidepressants in Parkinson’s disease.13

Electroconvulsive therapy (ECT) may produce simultaneous remission of comorbid depression and Parkinson’s disease. Case reports, case series, and one sham-ECT controlled trial indicate that ECT is effective for depression in Parkinson’s disease and may also improve motor function.14 Many patients will experience improvement in motor symptoms but the magnitude (sometimes dramatic) and duration (sometimes many months) of benefit are variable and unpredictable. Maintenance ECT has also been used to extend the motor benefits. The potential benefits of ECT in patients with Parkinson’s disease and depression must be balanced against the common side effects of delirium and treatment-emergent dyskinesia.



Anxiety is very common in Parkinson’s disease,15 particularly as the disease progresses with anticipatory anxiety about motor freezing. Whether antiparkinsonian medications themselves contribute to anxiety is not clear. Treatment with antidepressants and cognitive-behavioral therapy (CBT), particularly if delivered along with physical therapy, can be helpful, and benzodiazepines sometimes may be required. However, the optimal pharmacologic treatment for anxiety in patients with Parkinson’s disease has not been established.1,15


Multiple Sclerosis

Multiple sclerosis is the most prevalent chronic disabling central nervous system disease in young adults, with a variable and unpredictable course. Common symptoms include motor and sensory dysfunction, visual loss, incontinence, and fatigue as well as cognitive impairment and mood symptoms. Psychiatric symptoms are common in multiple sclerosis and have significant effects on patients’ lives. (A more detailed review of psychiatric aspects of multiple sclerosis can be found elsewhere.16)



MDD occurs in patients with multiple sclerosis at approximately double the prevalence in the general population of comparable gender and age mix, and subsyndromal depressive symptoms are even more common. Between 25% and 50% of multiple sclerosis patients will have MDD sometime in their lives. However, depression remains underdiagnosed and undertreated in patient with multiple sclerosis. Suicide usually preceded by depression is not uncommon in multiple sclerosis, with one study estimating it may account for as many as 15% of deaths in patients with multiple sclerosis.17 Research to date has not clearly established whether the likelihood of depression is proportional to the degree of neurologic disability or duration of multiple sclerosis. As in stroke, there has been an attempt to differentiate “biologic” depression from “reactive” depression and to link the former to specific brain lesion sites. However, the literature remains unclear as to whether the risk of depression in multiple sclerosis can be related to lesions in specific brain areas.1,16

In patients with multiple sclerosis, depression causes greater cognitive dysfunction, poorer health-related quality of life and functional status, disruption of social networks, and reduced adherence with treatment. Such effects have been found in many other chronic diseases and it has not been demonstrated that depression affects the demyelination pathophysiology of multiple sclerosis, although depression may increase and its treatment decrease production of pro-inflammatory cytokines.18 The study of depression as an independent risk factor affecting the onset or course of multiple sclerosis is challenging because depression may also be a direct physiologically mediated consequence of the disease, a psychological reaction to the illness, or a complication of pharmacotherapy.19 Depression is especially difficult to study in multiple sclerosis because of its uncertain relationship to the multiple sclerosis-fatigue syndrome (discussed below).20

Both psychotherapy and pharmacotherapy appear to be effective for decreasing depressive symptoms in patients with multiple sclerosis,21 but studies to date have been few and small. In those studies, response rates to CBT have been equal to or better than than with antidepressant pharmacotherapy.


Bipolar Disorder

It has been long recognized that multiple sclerosis sometimes presented with mania, at times before other neurologic signs. However, some reported cases of bipolar disorder caused by multiple sclerosis may have been due to corticosteroid treatment, and some have represented other types of emotional lability caused by multiple sclerosis, such as emotional incontinence (see below). A limited epidemiologic literature has indicated that multiple sclerosis and bipolar disorder occur together at more than twice the expected rate based on their prevalence in the general population, but there have been no large, population-based epidemiologic studies of the prevalence of bipolar disorder in multiple sclerosis patients.16


Emotional Incontinence

Emotional incontinence (also referred to as pathologic crying or laughing, emotional diarrhea, emotional lability, pseudobulbar affect, or, more recently, involuntary emotional expression disorder [IEED]22) is a syndrome of uncontrollable episodes of emotional expression that occurs in up to 10% of multiple sclerosis patients23 and in a variety of other neurologic conditions including stroke.3 IEED is characterized by episodes of crying or laughing that are unrelated to or disproportionate to the patient’s actual emotional state. The crying and/or laughing are disinhibited and experienced by the patient as ego-dystonic and a struggle to stop. This form of emotional lability has been theorized to result from damage to inhibitory neurons projecting from the frontal lobes to limbic areas. Pathologic crying or laughing can have a significant impact on individuals’ social functioning and their relationships with others. Unpredictable and uncontrollable outbursts of affect often cause severe embarrassment and avoidance of social interactions and may result in subsequent agoraphobia. Treatment has usually been with TCAs or SSRIs, but dopamine agonists and a combination of dextromethorphan and quinidine have also been reported to be helpful.24



While anxiety symptoms and disorders are common in multiple sclerosis, as with most chronic medical illnesses they have received much less study than depression. Clinically significant current anxiety has been reported in 25% to 40% of multiple sclerosis patients, and the lifetime risk of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,25 anxiety disorders is approximately 50% greater than in the general population.16,26 Like depression, anxiety disorders are underrecognized and undertreated in multiple sclerosis.


Cognitive Dysfunction

Cognitive impairment may ultimately affect 50% of all patients with multiple sclerosis, with the deficits reflecting the subcortical location of the demyelination, including impairment of attention, speed of processing, and executive functions.1 Disorders of working memory may be prominent, and a minority of patients become frankly demented. However, cognitive impairment in multiple sclerosis may also be due to fatigue, depression, anxiety, or medication side effects. Neuropsychological assessment in multiple sclerosis patients with cognitive dysfunction can be helpful in this differential diagnosis as well as prognosis.



Fatigue is the most common symptom in multiple sclerosis, affecting 80% of patients and ranging from mild to disabling. While it is aggravated by heat and exertion, it is not eliminated by their avoidance. It should be distinguished from depression,20 medication side effects, and physical exhaustion and deconditioning attributable to motor impairment, though such distinctions are usually difficult and many patients have more than one of these contributing to their fatigue. The cause of multiple sclerosis-fatigue is unknown. Pharmacologic treatments include amantadine (100 mg twice daily), amphetamines and related stimulants (including pemoline, which is no longer available in the United States), SSRIs, and most recently modafinil,27 which is Food and Drug Administration-approved for the treatment of multiple sclerosis-related fatigue. A very gradually progressive exercise program, as in chronic-fatigue syndrome,28 can also be very helpful in multiple sclerosis.29



Both acute and chronic pain are common in multiple sclerosis and can be disabling. One study found that 25% of a large community-based sample of people with multiple sclerosis had severe chronic pain.30 Mechanisms may include dysesthesia, altered cognitive function, and other multiple sclerosis complications such as spasticity. Of the acute pain syndromes, trigeminal neuralgia is the most common and usually responds to carbamazepine.31 Widespread chronic pain is more common and harder to manage. Dysesthetic limb pain is particularly troublesome and treatment is usually with amitriptyline or gabapentin.


Psychiatric Side Effects of Treatment

Pharmacotherapy for multiple sclerosis may include corticosteroids, interferon, and other drugs. Corticosteroids have dose-related psychiatric adverse effects, including mania, depression, mixed states, psychosis, anxiety, insomnia, and delirium. A previous psychiatric reaction to corticosteroids does not necessarily predict recurrent reactions with subsequent steroids. The onset of psychiatric symptoms is typically within the first 2 weeks of treatment. Mild psychiatric side effects include insomnia, hyperexcitability, mood lability, mild euphoria, irritability, anxiety, agitation, and racing thoughts. Mood disorders are the most common psychiatric reaction to corticosteroids. Mania is also common and patients may experience both mania and depression during a single course of corticosteroid therapy. Affective symptoms are often accompanied by psychotic symptoms. Delirium and psychosis (without mood symptoms) are less common. Cognitive dysfunction also has been reported.

There are two types of interferon (IFN)-β used for the treatment of multiple sclerosis (IFN-β 1a and IFN-β 1b). While IFN-β commonly cause some of the same side effects as IFN-α (eg, flu-like symptoms), in contrast to IFN-α there is no clear evidence that IFN-β increase the risk for depression in patients with multiple sclerosis. Other drugs used to treat multiple sclerosis, including glatiramer acetate, mitoxantrone, and natalizumab, have not been reported to have neuropsychiatric side effects (except with the very rare cases of progressive multifocal leukoencephalopathy that occurred after natalizumab).16 PP



1. Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2. Carson AJ, Zeman A, Myles L Sharpe MC. Neurology and neurosurgery. In: Levenson, JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3. Levenson JL. Psychiatric issues in neurology, part I: stroke. Primary Psychiatry. 2007;14(9):37-40.
4. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716.
5. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. N Engl J Med. 1999;340(10):757-763.
6. Mancini F, Tassorelli C, Martignoni E, Moglia A, Nappi G, Cristina S, Pacchetti C. Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease. Clin Neuropharmacol. 2004;27(1):33-37.
7. Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Disord. 2006;21(12):2078-2081.
8. Sobow T. Parkinson’s disease-related visual hallucinations unresponsive to atypical antipsychotics treated with cholinesterase inhibitors: a case series. Neurol Neurochir Pol. 2007;41(3):276-279
9. Holroyd S, Currie LJ, Wooten GF. Depression is associated with impairment of ADL, not motor function in Parkinson disease. Neurology. 2005;64;2134-2135.
10. Errea JM, Ara JR. Depression and Parkinson disease [Spanish]. Rev Neurol. 1999;28(7);694-698.
11. Brooks DJ, Doder M. Depression in Parkinson’s disease. Curr Opin Neurol. 2001;14:465-470.
12. Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias.Neurology. 1999; 22;53(5):1154.
13. Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
14. Rasmussen KG, Rummans TA, Tsang TSM, Barnes RD. Electroconvulsive therapy. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:957-978.
15. Richard IH. Anxiety disorders in Parkinson’s disease. Adv Neurol. 2005;96:42-55.
16. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psych Clin N Am. In press.
17. Sadovnick AD, Eisen K, Ebers GC, Paty DW. Cause of death in patients attending multiple sclerosis clinics. Neurology. 1991;41(8):1193-1196.
18. Gold SM and Irwin MR. Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Neurol Clin. 2006;24(3):507-519.
19. Zorzon M, de Masi R, Nasuelli D, et al. Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects. J Neurol. 2001;248(5):416-421
20. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6(3):181-185.
21. Mohr DC, Goodkin DE. Treatment of depression in multiple sclerosis: review and meta-analysis. Clinical Psychology: Science and Practice. 1999;6:1-9.
22. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11(6):1-7.
23. Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997;54(9):1116-1121.
24. Brooks BR. Involuntary emotional expression disorder: treating the untreated. CNS Spectr. 2007;12(4 suppl 5):23-27.
25. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
26. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
27. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005;64(7):1139-1143.
28. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ. 2001;322(7283):387-390.
29. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39(4):432-433.
30. Ehde DM, Gibbons LE, Chwastiak L, Bombardier CH, Sullivan MD, Kraft GH. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler. 2003;9(6):605-611.
31. Thompson AJ. Symptomatic treatment in multiple sclerosis. Curr Opin Neurol. 1998;11(4):305-309.




Dr. Haridas is a final year resident, Dr. Oluwabusi is a Child Fellow, and Dr. Gurmu is Chief resident in the Psychiatry Program at Drexel University College of Medicine in Philadelphia. Dr. Kushon is Clinical Associate Professor of Psychiatry at Drexel University College of Medicine and Medical Director of the Psychiatric-Medical Care Unit at Hahnemann University Hospital in Philadelphia, Pennsylvania.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Off-label disclosure: This article includes discussion of investigational treatments for major depression.

Please direct all correspondence to: Arun Haridas, MD, MRCPsych, Drexel University College of Medicine, Department of Psychiatry, 1427 Vine St, 8th Floor, Philadelphia, PA 19107; Tel: 215-762-6660; Fax: 215-762-6673; E-mail: aharidas@drexelmed.edu.

Focus Points

• Several case reports point to quetiapine’s abuse potential on the black market.
• Oral, intravenous, and intranasal routes of abuse have been reported.
• The inhalational method of quetiapine abuse is novel and counter-intuitive.
• Polysubstance abuse history may bring combinations of abuse, eg, quetiapine with cocaine-“Q” ball, quetiapine with marijuana “Maq ball.”



Quetiapine abuse has been a cause for increased concern among clinicians. Several reports have highlighted this in the past. Reports of quetiapine abuse have varied in their routes of administration. The authors have had experience in managing several patients who have admitted to the use of quetiapine outside of prescription settings. This article examines the case of a recent patient on the authors’ inpatient unit who admitted to a novel route of abuse. While quetiapine’s abuse potential in the black market is well known, motivations for the abuse of quetiapine have varied in the past. Anxiety and insomnia has been amongst the reported motivations. Combination abuse of quetiapine with cocaine, called “Q ball,” have been reported previously. Quetiapine serves as a substitute for heroin when used in this combination. This article highlights a previously unreported combination of quetiapine with marijuana used in the inhalational route in what is termed a “Maq ball.”


Quetiapine has been cited in several recent reports of being abused, especially in prison settings under the name “baby heroin” and “quell.”1,2  Reports of quetiapine abuse have varied in their routes of administration from the intravenous,1 intranasal,3,4 and oral.5 The authors have had experience in managing numerous patients in the in-patient unit who have admitted to obtaining and using quetiapine outside of prescription settings. A recent patient in an in-patient unit is highlighted below, illustrating this worrisome trend.

Case Report

A 27-year-old Hispanic male was admitted to the in-patient unit with a history of worsening depressed mood with suicidal ideation. He described polysubstance abuse involving marijuana, crack cocaine, alprazolam, and quetiapine; his preferred drug of choice was marijuana. He described smoking 1 oz. of marijuana daily. Approximately 1–2 times per week, he smoked crushed quetiapine tablets mixed with one ounce of marijuana. In addition, he smoked crack cocaine 3 times/week and alprazolam 5–10 mg/day orally up to 5 times/week.

Efforts to stop his quetiapine on this admission were unsuccessful on the unit, though he agreed to a tapered discharge dosage of quetiapine 100 mg/day. He requested to be discharged to a local drug and alcohol recovery house. Examination of prior admission records revealed that 5 months earlier, he had admitted to using quetiapine from the black market. At the time, he abused quetiapine orally, taking ~2–3 pills of quetiapine 100 mg/day, in addition to being prescribed quetiapine 100 mg BID by his primary care physician for his mood symptoms.


Quetiapine is a drug of known value on the black market of antipsychotics.6 Its use is motivated by anxiety and insomnia.4 Quetiapine, amongst olanzapine, anticholinergics, and tricyclic antidepressants, have been a favored method to “zone out” or “take the edge off” amongst buyers in the black market.6 This may be related to the fact that quetiapine is associated with a better subjective response than its conventional antipsychotic counterparts.7

Quetiapine, crushed and mixed with cocaine and water, and taken intravenously, has been previously recorded in the literature as a “Q ball.”8 The strategy aims to mitigate the dysphoria associated with cocaine withdrawal through the sedative and anxiolytic effects of quetiapine. Quetiapine in the described case served as a substitute for heroin and the more classic cocaine and heroin “speed ball” combination.8


There have been no reports of quetiapine  combined with marijuana and serving as what we term a “Maq ball.” Unlike combining cocaine and quetiapine, which carries the risk for QT prolongation,8 lethal side effects are unlikely with this combination. However, it once again draws attention to this worrying trend of quetiapine becoming an increasing favorite for novel and hitherto unknown methods of abuse. Clinicians would do well to keep this fact in mind when deciding on an appropriate antipsychotic for individuals with comorbid substance use disorders. PP


1.    Hussain MZ, Waheed W, Hussain S. Intravenous quetiapine abuse. Am J Psychiatry. 2005;162(9):1755-1756.
2.    Del Paggio D. Psychotropic medication abuse in correctional facilities. The Bay Area Psychopharmacology Newsletter. 2005;8(1):5.
3.    Morin AK. Possible intranasal quetiapine misuse. Am J Health Syst Pharm. 2007;64(7):723-725.
4.    Pierre JM, Shnayder I, Wirshing DA, Wirshing WC. Intranasal quetiapine abuse. Am J Psychiatry. 2004;161(9):1718.
5.    Reeves RR, Brister JC. Additional evidence for the abuse potential of quetiapine. South Med J. 2007;100(8):834-836.
6.    Tarasoff G, Osti K. Black market value of antipsychotics, antidepressants and hypnotics in Las Vegas, Nevada. Am J Psychiatry. 2007;164(2):350.
7.    Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, Award A. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side effects profile and impact on quality of life. Schizophr Res. 2000;43(2-3):135-145.
8.    Waters BM, Joshi KG. Intravenous Quetiapine-Cocaine Use (“Q- Ball”). Am J Psychiatry. 2007;164(1):173-174.





Dr. IsHak is Director of Psychiatry Residency Training and Medical Student Education in Psychiatry at Cedars-Sinai Medical Center (CSMC) and Associate Clinical Professor of Psychiatry at the University of California, Los Angeles (UCLA), the University of Southern California, and CSMC, all in Los Angeles, California. Dr. Rasyidi is the CSMC Psychiatry Chief Resident. Dr. Saah is former research physician volunteer at CSMC and current psychiatry resident at Emory University in Atlanta, Georgia. Dr. Vasa is on medical staff at CSMC. Dr. Ettekal is Research Psychiatrist at California Clinical Trials in Glendale, California. Dr. Fan is Associate Director of Inpatient Psychiatry at CSMC and Assistant Clinical Professor of Psychiatry at UCLA and CSMC.

Disclosures: Dr. IsHak receives grant support from the National Alliance for Research on Schizophrenia and Depression and Pfizer. Drs. Saah, Rasyidi, Vasa, Ettekal, and Fan report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Waguih William IsHak, MD, FAPA, Cedars-Sinai Medical Center, Department of Psychiatry and Behavioral Neurosciences, 8730 Alden Dr, Thalians W-157, Los Angeles, CA 90048; Tel: 310-423-3515; Fax: 310-423-3947; E-mail: Waguih.IsHak@cshs.org.

Focus Points

• Factitious disorder is the intentional production of symptoms to assume the sick role in the absence of secondary gain.
• Factitious disorder could present with physical, psychological, or combined symptoms.
• Factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering.
• Medical records from previous hospitalizations and healthcare providers are essential.
• Factitious disorder needs to be suspected in frequent acute care utilizers with atypical presentations and negative results.



In the clinical setting, factitious disorder is often mistaken for malingering or somatoform disorders. Three cases of factitious disorder with physical, psychological, and combined symptoms are reported. Comparing these patients may help facilitate identification of factitious disorder, especially with improving recognition in patients who are high utilizers of acute medical and psychiatric services. A high level of suspicion regarding the diagnosis of factitious disorder is needed, especially in cases with frequent utilizers of emergency room and inpatient services, atypical presentations, and negative diagnostic results.


The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision,1 refined the diagnosis for factitious disorder by providing three diagnostic criteria (Table 1).2 Studies indicate a .5% to .8% prevalence of factitious disorders in hospital patients, with a prevalence of up to 6% to 8% on psychiatric units.2-5 However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. Due to diagnostic difficulties, only the most severe cases of factitious disorder are diagnosed correctly. In other cases, factitious disorder may be suspected but not diagnosed. The following three cases of factitious disorder with disparate presentations are based on the subtypes described in the DSM-IV-TR (Table 2).1 Patient A presented with mainly physical symptoms. Patient B presented with physical and psychological symptoms. Patient C presented with mainly psychological symptoms. The patients presented depict the wide spectrum of severity and presentations in factitious disorders that contribute to the difficulty of accurate diagnosis. The management of these cases also demonstrates the diagnostic strategy needed for improving diagnosis of factitious disorder.


Factitious Disorder Case Reports

Patient A: Factitious Disorder with Predominantly Physical Signs and Symptoms

Patient A, a 27-year-old female, would often present to the emergency department with vague complaints of abdominal pain and bright red blood per rectum, which she stated was typical for her Crohn’s disease. The patient also freely reported a psychiatric history with multiple diagnoses, including bipolar disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, a history of anorexia nervosa, and Asperger’s syndrome, as well as a history of suicide attempts and self-injurious behaviors. The patient had a stable income through state disability and lived in a comfortable home with her parents in an affluent neighborhood. Psychiatric consultation was requested on her third admission to the medical center and after 13 previous presentations to the emergency department. At that point she had undergone extensive diagnostic testing, including computed tomography scans, upper gastrointestinal (GI) endoscopy with small bowel follow through, colonoscopy, and biopsies, all of which had been unsuccessful in finding the cause of GI bleeding. She was transferred to the inpatient psychiatric hospital for complaints of depressed mood and her diagnosis was refined to PTSD and borderline personality disorder. During hospitalization, a nurse found the patient in the bathroom one night inserting a toothbrush into her rectum, producing the bloody stools that she had been complaining of for the past several days. When confronted, the patient articulated that she desired the attention that came with her medical work-ups and that it instilled a sense of control over her environment. This behavior was different from previous suicide attempts in that there was no intent to die. It was also distinct from her self-injurious behaviors which were performed openly and freely admitted to. As for the discrepancy between reported psychiatric diagnoses and those at time of discharge, this was due to diagnostic errors on the part of previous treatment teams, not due to misrepresentation by the patient. The patient thus met criteria for factitious disorder with predominantly physical symptoms.

Patient B: Factitious Disorder with Combined Psychological and Physical Signs and Symptoms

Patient B, a 52-year-old female with bipolar depression, was admitted to the inpatient unit for the fifth time in 6 months after presenting with suicidality and depressed mood. The patient stated that she had been diagnosed with OCD, PTSD, and attention-deficit/hyperactivity disorder. She also stated that she was blind and had a guide dog. During hospitalization, she consistently reported that her depression and suicidality were worsening. However, observations showed that the patient joked, laughed, and regaled others with far-fetched stories. She ate and slept well, and ambulated without difficulty. It also became increasingly obvious that Patient B was not blind. She was observed reading, looking in the mirror, and dialing numbers from her phone book. In daily sessions, inconsistencies were noted in her elaborate recollections of traumas. The management plan consisted of performing a diagnostic work-up including medical, neurologic, and neuropsychological evaluations, in addition to a trial of citalopram 40 mg PO and lamotrigine 200 mg PO, both at bedtime, as well as psychotherapy. Ophthalmology and neurology consults did not reveal any visual loss. The psychological and neuropsychological testing confirmed suspicions about the presence of significant antisocial, narcissistic, and borderline personality traits, and showed intact neuro-cognitive functioning. Additional information confirmed the patient’s tendency to move from hospital to hospital, leave against medical advice, and express inconsistent medical and psychiatric complaints, which gave evidence to the diagnosis of a factitious disorder. The most important two differential diagnoses were conversion disorder and malingering. Conversion disorder was ruled out because the patient was shown to have intact vision on medical consultations. Regarding malingering, there were no specific secondary gains as she had a stable housing and financial situation. It became clear that Patient B was intentionally producing both physical (blindness) and psychological (worsening of depression) symptoms in order to assume the sick role. She was informed of the diagnostic possibility of factitious disorder with combined psychological and physical signs and symptoms, and was recommended for continuation of both psychotherapy and pharmacotherapy.

Patient C: Factitious Disorder with Predominantly Psychological Signs and Symptoms

Patient C, a 38-year-old male, presented complaining of a 3–4-month history of depressed mood, poor energy, difficulty sleeping, poor appetite, psychomotor retardation, increasing hopelessness, and suicidal ideation with a plan to walk into traffic. Once on the inpatient wards, the patient remained compliant with his medications; however, no change in mood was seen. Throughout his stay, Patient C demonstrated, on a consistent basis, a discrepancy between what he stated to staff and what was observed on the wards. The patient consistently reported depressed mood and suicidality, but was observed to be euthymic, in good spirits, and carousing with the other patients. The patient’s stay was also significant for two suicide attempts both with low lethality and high possibility of rescue. Elaborate stories regarding the death of his best friend, as well as his previous married life, employment status, and relations with his family, were for the most part later repudiated by the patient’s father. Eventually, the patient was so disruptive to the inpatient milieu that he was placed in seclusion. Within a few hours he arranged to be picked up by a friend and was successful in finding a place to stay. Before being discharged, the patient admitted to never being suicidal and that the two suicide attempts had both been feigned. The treatment team noticed that the patient had traits of antisocial, narcissistic, borderline, and histrionic personality disorders. The likelihood of malingering was low because the patient had stable income and was offered numerous housing options, which he refused. The treatment team concluded that this patient was willing to assume the sick role, by intentionally manifesting psychological symptoms, to gain the social interaction of being in a psychiatric unit.


Although factitious disorders have been formally recognized for >30 years, diagnostic criteria have evolved significantly since the recognition of the disorder. From the DSM-II6 through the DSM-III7 and DSM-III-R,8 factitious disorders had no clear inclusion or exclusion criteria for diagnosis.9 The advent of the DSM-IV10 and DSM-IV-TR11 advanced the diagnosis of factitious disorder by defining three diagnostic criteria: A) intentional production of physical or psychological signs or symptoms, B) motivation to assume the sick role, and C) absence of external incentives or secondary gain.1,12-14 Criterion A differentiates factitious disorder from somatoform disorders by requiring the intentional production of signs or symptoms. Criterion C differentiates factitious disorder from malingering by eliminating the presence of secondary gains for the patient.15 It is also important to note that while patient cases B and C were also clear examples of pseudologia fantastica, where embellished truth and colorful fantasies are presented as fact in order to gain the interest of the listener, this phenomenon is neither pathognomonic nor necessary under our current nosology for the diagnosis of factitious disorder.14

The three cases presented elucidate several effective diagnostic strategies. With Patient A, psychiatric consultation led to psychiatric hospitalization and a careful review of the medical and psychiatric history. The treating psychiatrist had thoughtful discussions with the patient’s other doctors, which confirmed her history of high health services, utilization, and a lack of evidence for a medical etiology. The close observation of the psychiatric nursing staff then caught the patient in an act of self-injury. With Patient B, the treating psychiatrist also had a thorough diagnostic plan, which included consultation with the neurology, medicine, ophthalmology, and neuropsychological testing services. Nursing observations on the inpatient psychiatric unit revealed that the patient did not have the visual or depressive symptoms that she claimed to have. The treating psychiatrist was also able to obtain valuable medical and psychiatric history from collateral sources to confirm a pattern of multiple hospitalizations, inconsistent medical and psychiatric presentations, and hospital discharges against medical advice. With Patient C, nursing observations also found that the patient’s behavior on the psychiatric unit were inconsistent with his reported symptoms. The treating psychiatrist was able to obtain collateral history from the patient’s father, which confirmed that the patient had falsified his symptoms and psychiatric history to gain admission to the psychiatric unit.

The growing literature on factitious disorder indicates that patients have certain common traits. Understanding these traits may help in accurate diagnosis and management. Some studies have found that factitious disorder patients often have work experience in healthcare fields. They can use their medical knowledge to deceive and confuse the treatment team in their search for an accurate diagnosis. Factitious disorder patients are fearful of abandonment and highly sensitive to rejection.16 They usually have comorbid Axis I and II diagnoses. They use the hospital setting to find support, safety, and social relationships that they cannot obtain otherwise. Confronted with their falsification of history and intentional production of symptoms, factitious disorder patients have increased risk of self-harm and exacerbation of psychiatric disorders. They become extremely difficult to manage as the therapeutic rapport is broken.

From the three patients presented and a review of the literature, several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder patients have been provided. In cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. After Patient A had been caught in the act of producing her physical symptoms, she conceded consent. However, even in situations where patients are caught “red-handed,” there may be an impressive level of denial with patients going so far as to assert that events never actually took place. With Patients B and C, consent was obtained by explaining to the patients that access to sufficient information was necessary in providing appropriate treatment. Again, there may be scenarios where patients balk at this proposal. Refusal by the patient of a well-presented, reasonable request should make the treating physician suspicious of a non-medical diagnosis. Similarly, the treating physician should also ask the patient for permission to collect history from collateral sources such as family members, spouses, and friends. A refusal by the patient may indicate a fear of discovering a falsification. In a hospital, the treating physician should ask the nursing staff to closely monitor a patient suspected of factitious disorder. Close observation can reveal a patient’s surreptitious production of clinical signs. The treating physician should also seek consultations from specialists in other fields to exclude a medical etiology for the patient’s signs and symptoms. In a psychiatric unit, the treatment team, including nurses and therapists, needs to be reminded to set appropriate limits and boundaries for suspected factitious disorder patients. These limits and boundaries may decrease the social and psychological gains that a patient may want from a hospitalization.


The dearth of information available on factitious disorder and the difficulty in obtaining epidemiologic and diagnostic information should not preclude the possibility of more accurate diagnosis and better management. Large descriptive and longitudinal studies with adequate diagnostic work-ups, including medical, neurologic, neuropsychological, and personality testing evaluations, are needed in order to develop a clear understanding of factitious disorders. Unfortunately, such studies are very difficult to undertake in a patient population that is adverse to discovery. Nonetheless, factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services. PP


1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:513-516.
2. Hamilton JC, Feldman MD, Janata JW. The A, B, C’s of factitious disorder: a 220 response to Turner. Medscape J Med. 2009;11(1):27.
3. Catalina ML, Gómez Macias V, de Cos A. Prevalence of factitious disorder with psychological symptoms in hospitalized patients. Actas Esp Psiquiatr. 2008;36(6):345-349.
4. Sutherland AJ, Rodin GM. Factitious disorders in a general hospital setting: clinical features and a review of the literature. Psychosomatics. 1990;31(4):392-399.
5. Gregory RJ, Jindal S. Factitious disorder on an inpatient psychiatry ward. Am J Orthopsychiatry. 2006;76(1):31-36.
6. Diagnostic and Statistical Manual of Mental Disorders. 2nd ed. Washington, DC: American Psychiatric Association; 1968.
7. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
8. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.
9. Rogers R, Bagby RM, Rector N. Diagnostic legitimacy of factitious disorder with psychological symptoms. Am J Psychiatry. 1989;146(10):1312-1314.
10. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
11. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
12. Krahn LE, Li H, O’Connor MK. Patients who strive to be ill: factitious disorder with physical symptoms. Am J Psychiatry. 2003;160(6):1163-1168.
13. Dike CC, Baranoski M, Griffith EE. Pathological lying revisited. J Am Acad Psychiatry Law. 2005;33(3):342-349.
14. Turner MA. Factitious disorders: reformulating the DSM-IV criteria. Psychosomatics. 2006;47(1):23-32.
15. Drob SL, Meehan KB, Waxman SE. Clinical and conceptual problems in the attribution of malingering in forensic evaluations. J Am Acad Psychiatry Law. 2009;37(1):98-106.
16. Feldman MD. Playing Sick? Untangling the Web of Munchausen Syndrome, Munchausen by Proxy, Malingering, and Factitious Disorder. New York, NY: Brunner–Routledge; 2004.



Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please e-mail questions or comments for Dr. Sussman to ns@mblcommunications.com.

It is a point I have made before, but the content of this month’s Primary Psychiatry reminds me of how important it is for those who diagnose and treat patients with mental disorders know those disorders and their treatments well. As primary care physicians (PCPs) increasingly treat psychiatric disorders, it is important to remember that many conditions and their treatment require full knowledge of differential diagnoses, even of rarely occurring disorders, as well as infrequent but potentially serious side effects of treatment.

Four years ago, a case report1 in our sister publication, CNS Spectrums, described a case of tardive dyskinesia (TD) associated with the long-term use of adjuvant aripiprazole in a patient with refractory depression. The authors wrote:

“Prior to the case of Mrs. C, there were no reports of aripiprazole-associated TD. In this report, however, we described the case of a woman who developed TD after 18 months of treatment with aripiprazole, and suggest that use of aripiprazole may be associated with this adverse effect. Clinicians who choose to prescribe aripiprazole as a primary antipsychotic agent or as an adjuvant treatment should be aware of the risk of TD.”

Shortly after the publication of this case report, aripiprazole became the first drug of any kind to be approved by the Food and Drug Administration as an addition to antidepressants for adults with major depressive disorder. Even though aripiprazole is an atypical antipsychotic, and there is a known risk of TD associated with these agents, published data have suggested that this risk is significantly lower than the risk of TD associated with older antipsychotics. This has made may clinicians comfortable using atypical antipsychotics as adjuncts in place of other add-on strategies. In fact, some early reports2,3 indicated that aripiprazole could cause improvement of TD.

In a Web-exclusive Letter to the Editor, Joseph H. Friedman, MD, and Daniel Tarsy, MD, express concern that increased use of aripiprazole by PCPs—a consequence of its FDA-approved indication for depression—increases the incidence of TD cases because, unlike psychiatrists, PCPs are not adequately accustomed to monitoring their patients for early signs of TD and do not counsel their patients about this risk.

They note that TD may occur in patients never treated with another dopamine antagonist, and even at the low doses recommended for treating depression. Although aripiprazole-associated TD may be reversible in some cases, in other cases the movement disorder may be permanent. They emphatically conclude that aripiprazole should only be used for refractory cases by doctors knowledgeable about antipsychotics. The dose should be as low as possible, and once the patient has achieved a stable improvement attempts should be made to wean off the drug. Alternatives include switching to other antidepressants, including the tricyclics, combined therapy with drugs of different chemical families, adjunctive exercise, and psychotherapy. They further note that psychiatrists should consider other alternatives, such as lithium or thyroid augmentation and that TD should be specifically evaluated and commented upon at each office visit so that the drug may be stopped if TD begins. It is worth noting that there are no data that compare either the safety or efficacy of long-term adjunctive atypical antipsychotic therapy with alternative combinations mentioned above.

In this issue, Waguih William IsHak, MD, and colleagues, in a case series on factitious disorder, describe three cases in which there is the intentional production of symptoms to assume the sick role in the absence of secondary gain. The disorder can present with physical, psychological, or combined symptoms. Like panic disorder, factitious disorders are commonly misdiagnosed with medical conditions or diagnosed as somatoform disorders or malingering. The authors note a .5% to .8% prevalence of factitious disorders in hospital patients, and a prevalence of up to 6% to 8% on psychiatric units. However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. They nevertheless feel that only the most severe cases of factitious disorder are diagnosed correctly. They report on three cases of factitious disorder subtypes, each with a unique disparate presentation, but yet sharing some common clinical features. They also provide several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder in patients. Most importantly, in cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. The authors conclude that factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services.

Raymond A. Lorenz, PharmD, and colleagues review the safety of varenicline in patients with mental illness. Varenicline is the most recently FDA-approved smoking cessation aid. However, it carries a boxed warning on its package labeling detailing the increased risk of psychiatric adverse events. Although the risk of developing psychiatric adverse events in the general population is relatively rare, the data presented in this article suggest that the risk for developing psychiatric adverse events is greater for those with pre-existing mental illness. This may not have been evident immediately after the drug came to market because patients with psychiatric conditions were excluded from the phase III clinical trials. Recognition of these rare adverse drug events are thus a result of post-marketing experiences. Thus, the authors caution that while varenicline is effective for facilitating smoking cessation, it may carry some serious risks, particularly for patients with preexisting mental illness. In the absence of clinical trials involving psychiatric patients, they conclude, the data reviewed in this article should lead to cautious use of varenicline in patients with mental illness, especially when the drug is used for extended periods of time.

A different type of smoking-related problem is discussed by Arun Haridas, MD, and colleagues. Quetiapine has been cited in several reports as being abused. This case report highlights a patient with a unique method of abusing quetiapine. The drug is relatively unique among antipsychotics in that it has value in the black market. It is used illicitly mainly as an anxiolytic or hypnotic, or to “take the edge off” amongst buyers in the black market. Quetiapine crushed and mixed with cocaine and water and taken intravenously has been termed a “Q ball,” and is used to mitigate the dysphoria associated with cocaine withdrawal. The authors describe quetiapine combined with marijuana, serving as what they term a “Maq ball.” They note that unlike the cocaine and quetiapine combination, which carries the risk for QT prolongation, lethal side effects are unlikely with this combination. However, they caution that clinicians would do well to keep the street use of quetiapine in mind when selecting antipsychotics for individuals with comorbid substance use disorders.

Robert Lasser, MD, and colleagues, all employees of Shire Development Inc., as disclosed in their conflict of interest disclosure, present an analysis of data—not the results of prospective and quantitative comparison studies—that suggests that lisdexamfetamine dimesylate may offer advantages over mixed amphetamine salts-extended release for the treatment of adults with attention-deficit/hyperactivity disorder.

I also encourage you to read the exchange of letters between Roger Z. Samuel, MD, and Kiki Chang, MD, regarding my recent interview with Dr. Chang on the topic of bipolar disorder in youths. PP


1. Maytal M, Michael Ostacher M, Stern TA. Aripiprazole-Related Tardive Dyskinesia. CNS Spectr. 2006;11(6)435-439.
2. Witschy JK, Winter AS. Improvement in tardive dyskinesia with aripiprazole use. Can J Psychiatry. 2005;50(3):188.
3. Duggal HS. Aripiprazole-induced improvement in tardive dyskinesia. Can J Psychiatry. 2003;48(11):771-772.



Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please e-mail questions or comments for Dr. Sussman to ns@mblcommunications.com.


As a clinician/educator, I am very aware of the limitations of textbooks and industry-sponsored clinical trials in addressing common challenges to treating patients with mental disorders. I am a big fan of the letters to the editor sections of journals and brief case reports. As editor of this journal, I am therefore gratified at the increase in correspondence and unsolicited papers that we have been receiving from readers of Primary Psychiatry. This is reflected in this issue of the journal, where there are no invited articles. The content of this issue addresses the kinds of clinical situations that we may confront in clinical practice.

The selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are known to impair clotting and produce a variety of bleeding abnormalities. While both case reports and reviews of large patient populations have been published over the past decade, many clinicians remain unaware of the increased risk of bleeding events associated with use of these drugs. These abnormalities are the result of impaired platelet function, although platelet count remains normal. In this issue, Ashish Aggarwal, MD, and colleagues present a case of ecchymoses associated with paroxetine 25 mg/day that remitted after a switch to a tricyclic antidepressant. Publication of this report is intended to remind clinicians to remain alert for hematological side effects when these drugs are used. As the authors note, most cases of bleeding involve the gastrointestinal tract. Risk is increased with concomitant use of non-steroid anti-inflammatory drugs and anticoagulant therapy, as well as in patients with liver disease. The authors review theories about the underlying cause of the bleeding abnormalities. Inhibition of the serotonin transporter on the platelet cell membranes, they hypothesize, leads to a depletion of serotonin in the platelets, which in turn decreases coagulation and may lead to a bleeding tendency in vulnerable individuals. Other possible mechanisms include inhibition of nitric oxide synthase, and hyperserotonemia-induced skin and mucous membrane lesions.

Kanwaldeep Sidhu, MD, and colleagues submit a case report of rash associated with risperidone long-acting injection (RLAI). They present a case of a 26-year-old male who developed a diffuse erythematous and maculopapular skin rash on both arms after initiation of RLAI treatment. Previous exposure to oral risperidone was uneventful. In this case, RLAI treatment was discontinued and diphenhydramine was prescribed, resulting in the rash disappearing completely in 3 weeks. A re-challenge with oral risperidone produced no rash and was clinically effective, suggesting that other ingredients in the solute and delivery system were responsible for this adverse effect.

Dopamine agonists have long been used in the treatment of affective disorders, mainly as add-on therapy. Matthew L. Prowler, MD, and Claudia F. Baldassano, MD, report three cases involving the use of pramipexole—a dopamine agonist Food and Drug Administration-approved to treat Parkinson’s disease and restless legs syndrome—to treat rapid cycling bipolar disorder. They cite reports that pramipexole can provide a beneficial role in bipolar depression, but note there have been no studies of this compound for use in rapid cycling bipolar disorder. They present cases of pramipexole augmentation in rapid cyclers with an active depressive episode. They report a positive response to treatment without cycle induction or acceleration. Effective doses were between 1.5–3.0 mg. At a higher dose, there were signs of emergent hypomania in one patient, which resolved with dose reduction.

Anthony T. Ng, MD, and colleagues present a review article on clinical challenges in the pharmacologic management of agitation. No drug is specifically approved as a treatment for agitation. Most treatment guidelines encourage reliance of behavioral intervention, such as verbal de-escalation and seclusion, as the initial approach for management of agitated patients. However, these techniques are often ineffective, and drug treatment becomes necessary. This article reviews the clinical challenges in managing agitation in the emergency setting. The authors observe that no currently available single agent or combination matches the characteristics of an ideal acute intervention for agitation, which include being easy to administer and not traumatic; rapid onset of action and a sufficient duration of action to allow for transport of patients to appropriate services; provision of tranquilization without excessive sedation that may interfere with patient interaction, diagnosis, and selection of additional therapy; and low risk for significant adverse reactions and drug interactions. They call for further study of alternative therapies for acute agitation that address some or all of these limitations.

La Vonne A. Downey, PhD, and colleagues examine the differences in how psychiatric patients come into the emergency department. The purpose of their study was to determine if there is a difference in the type of psychiatric patient transported via emergency medical service (EMS) as compared to police or walk in. A secondary purpose was to determine if staff was injured during EMS transport. They hoped to determine if there is a significant difference between patients transported by EMS as compared to those who were transported by other means. A total of 300 patients were evaluated. The authors report that the EMS system is frequently used to transport intoxicated patients, who do not have a regular psychiatrist, have an admitting diagnosis of drug use, and are later discharged from the emergency department (ED). These findings could be used to alert ED staff that the psychiatric patient brought in by EMS or police present differently than the majority of psychiatric patients who walk in or are brought by family members. This information could be used further to develop a treatment protocol to assist the ED staff addressing the needs of these patients.

In a letter to the editor, Daniel J. Rapport, MD, anticipates upcoming changes in the classification and diagnostic criteria for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.1 He proposes a pathogenic model of cycle frequency that distinguishes cycling from non-cycling mood disorders. More specifically, he reiterates a widely held view that spontaneous, highly recurrent mood disorders are the result of kindling and should be diagnosed as such based on the concepts. He concludes that when we see this pattern of high-frequency, spontaneous mood recurrences we should consider the addition of mood stabilers and atypical antipsychotics to re-stabilize the “emotional thermostat.”  PP



1.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; In press.


Dr. Downey is associate professor of Health Services/Public Administration at Roosevelt University in Chicago, Illinois. Dr. Zun is chairman and professor in the Department of Emergency Medicine at Finch University/Chicago Medical School and chairman in the Department of Emergency Medicine at Mount Sinai Hospital in Chicago. Ms. Burke is a clerk and clinical research coordinator in the Department of Emergency Medicine at the Rosalind Franklin University of Medicine and Science at Chicago Medical School.

Disclosures: Dr. Downey and Ms. Burke report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Zun is a consultant to Alexza Pharma and on the speaker’s bureau of sanofi-aventis.

Please direct all correspondence to: La Vonne Downey, PhD, Roosevelt University, School of Policy Studies, 430 Michigan Ave, Chicago, IL 60605; Tel: 847-360-1003; E-mail: Ldowney@roosevelt.edu.



Objective: The purpose of the study was to determine if there is a difference in the type of psychiatric patient transported via emergency medical service (EMS) as compared to police or walk in. The secondary purpose was to determine if staff was injured during EMS transport. The hypothesis was to determine if there is a significant difference between patients transported by EMS as compared to those who were transported by other means.

Methods: This study was a retrospective emergency department (ED) chart and EMS-run review performed in an urban community teaching hospital with 45,000 annual emergency department visits. Demographics, history and physical examination, patient and staff injuries, and interventions were reviewed. The participants were patients who entered the ED with a psychiatric diagnosis. Patients who were seen with other complaints were excluded. The data analysis included descriptive, frequencies, and analysis of variance.

Results: Three hundred patients were evaluated. Analysis of patients transported by EMS versus police, walk-ins, or those brought in by family or other means demonstrated significant difference in regular doctor, regular psychiatrist, drug and use, patients restrained, alcohol level, marital status, disposition, age ,and admitting diagnosis using a significance level of <.05. There was no significant difference between transport means and urine drug test, type of restraint, violent intent, gender, ethnicity, insurance, cost, or throughput.

Conclusion: This study found that the EMS system was more frequently used to transport intoxicated patients, who do not have a regular psychiatrist, have an admitting diagnosis of drug use, and are later discharged from the emergency department. The study did not find, due to lack of documentation, physical harm to police and EMS personal.

Focus Points

• There is a difference in the types of patients brought in by police, emergency medical service, or family members or those who walk in on their own accord.
• The knowledge of these differences can help assist the emergency department (ED) staff in their treatment plan for those patients.
• The knowledge of the difference in psychiatric patients who present to the ED can be used to train ED staff and based on further studies help to develop treatment protocols.



Patients with psychiatric complaints frequently present to the emergency department (ED) via various means. Many of these psychiatric patients exhibit agitation and violent behavior.1 The number of psychiatric patients transported by emergency medical service (EMS) within the United States in not known. However, one study2 estimates 10% to 15% of EMS calls were for psychiatric patients. Grange and Corbett3 showed that EMS providers are exposed to violent behavior when performing their jobs at a rate of 8%, with 50% of the violent behavior directed against pre-hospital personal. Trinalli4 found that the potential for injury to prehospital providers from violent patients is widespread and at present there is no mechanism for identifying violent patients.

Fire or police personnel bring many psychiatric patients into the ED. These personnel may use means to control patients’ behavior during transportation, including handcuffs. Many EMS systems have standing orders to apply restraints to patients. The National Association of EMS physician prescribes the proper means to restrain patients.5 Cheney and colleagues6 demonstrated compliance with protocols for psychiatric transports has been poor even though EMS providers had a high level of concern for patient safety.

The range of injuries was studied by the National Association of EMS Physicians and National Association of State EMS directors in a 2002 report.7 Patients accounted for 89% of violent behavior, including verbal (20%), physical (48%), and both verbal and physical (30%) assaults.3,5 Factors that were found to predict violence were the presence of police and psychiatric disorders.3,8-10

The purpose of this study was to determine if there is any difference in the type of patients presenting to the ED with psychiatric complaints who are brought by police, fire department, family, walk-in, or other. The hypothesis was that patients transported by EMS were significantly different than those transported by other means. The secondary purpose was to determine whether the EMS patient or staff were injured during the transportation process.



This was a retrospective chart review of a random sample of psychiatric patients transported by fire, police, family, walk-in, or other during 1 year at a level-one adult and pediatric ED that serves 45,000 annually. Any patient with a psychiatric diagnosis in the ED diagnosed by the emergency physician was included in the study. Psychiatric complaints for inclusion are those noted in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.11 The diagnoses may include the following presenting complaints: psychiatric illness, altered mental status, depression, psychosis, bizarre or inappropriate behavior, violence, agitation, substance abuse, and suicidal or homicidal ideation. The psychiatric diagnosis must be the first or second provisional diagnosis on the ED chart. Those patients who present with other complaints or from inter-hospital transfers were excluded. Patient identifiers were removed from all charts. Patients were selected from a 1-year period. They were then randomizated by enrolling every fourth patient in the study with each month during the 1-year time period.

The ED charts and paramedic run sheet were used as a primary source of data. Basic demographic data was collected, including age, gender, race, time of day, time of week, and transport mechanism. Any treatment or intervention that the patient received, including oxygen, intravenous fluids, drug administration, or police intervention and/or restraints was documented. Hospital charges were noted. Injuries to self, staff, or family were also recorded, if documented.

An analysis using the Statistical Package for Social Sciences was used to determine if there were any significant relationships between the following: treatment; restraints; patient presentation; treatments during transportation; and injuries to patient, staff, or family as it relates to differences in transportation. This study was Institutional Review Board approved.



Three hundred patients were enrolled in the study. The majority were evaluated: 102 walk-ins, 66 from EMS, 82 from police, 36 brought by family, and 14 by private ambulance. The breakdown of patients transported by EMS or police was as follows: male (51.6%), mean age of 41.7 years, single (77.3%), African American (71.2%), without a regular doctor (36.4%) or regular psychiatrist (13.6%), admitted with a diagnosis of drug use (42.4%), restrained (68.2%), with a positive alcohol level (42.4%), and discharged home (47.0%). The mean charges were $6,304, and the average time that patients spent in the ED was 506 minutes. See Tables 1–6 for more specific breakdowns.

Their payment sources varied with 54% having Medicaid and 26% being self-pay. Thirty percent of those that were self-pay walked in and the remaining seventy percent of self-pay were brought in by the fire or police departments. The majority of patients had some type of federal or state coverage such as Medicaid, Medicare, and/or the state Comprehensive Health Insurance Plan (specifically to the state of Illinois). Patients with insurance were more likely to walk in (38%), with 20% being brought by the fire department and 34% by the police.

Patients with differing diagnoses came by different means. Those patients with affective psychosis, which made up 38% of all patients, were brought in by themselves (44%), the police (26%), fire department (15%), or family (14%). Patients with schizophrenic disorders were brought in by police (50%), themselves (31%), or family members (9%). Two admitting diagnosis, alcohol dependency syndrome and nondependent abuse of drugs, were most likely brought by the fire department followed by the police; very few were walk-ins or brought by family members. The fire department also brought in 48% of those who tested positive for alcohol. The remaining patients who tested positive for alcohol either walked in or were brought by the police. Restrained patients were more likely to be brought in by the police (43%), followed by the fire department (22%) and themselves (22%).

Analysis of patients transported by EMS versus police or walk-ins demonstrated significant difference in the following: regular doctor, regular psychiatrist, drug use, patients restrained, alcohol level, marital status, disposition, age, and admitting diagnosis using a significance level of <.05. Due to the mixture of continuous and dichotomous variables, an analysis of variance was used to determine what, if any, significant differences occurred between those patients who arrived via EMS, police, family, or walk-in. There was a significant difference between how a patient was brought to the ED and principle diagnosis F=5.32 P=.000, having a regular doctor F=6.23 P=.000, having a regular psychiatrist F=4.49, P=.01, alcohol levels F= 4.89 P=.000, admitted illicit drug use F=2.69 P=.02, age F=2.95 P=.013, marital status F=3.18 P=.008, disposition from the ED F=7.47 P=.000, and behavioral restraints used F=4.55, P=.001. There was no significant difference between transport means and urine drug test, type of restraint, violent intent, gender, ethnicity, insurance, cost, or throughput. [See Tables 7–11, which can be found after the references.]11



This study found that there is a difference in the type of psychiatric patient transported via EMS as compared to those brought in by police, family, or themselves. Patients transported by EMS were more likely to not have a regular doctor or psychiatrist, be single, be diagnosed as schizophrenics, have drug and alcohol dependency issues, need behavioral or chemical restraints, and be self pay. Grange and colleagues3 found that patients brought by EMS and police were not the majority of psychiatric patients that presented to the ED. They were different than the majority who walk in or are brought by family members. They found that these patients were more likely to have a comorbid substance use diagnosis which could impact the need for restraints.

This difference may help explain the studies that have demonstrated the high rate of injury of patients transported by EMS personnel. Tintanilli4 found that 67% of emergency medical technicians were injured transporting violent patients. Cheney and colleagues6 found an association between EMS injury and prior history of psychiatric illness. Unfortunately, due to lack of documentation, this study did not find physical harm to police and EMS personal.

This study, however did find that patients who needed restraint and drug or alcohol intoxication were more often transported by EMS. Since these findings are based on only 300 subjects, it would be inaccurate to extrapolate outward to say that all patients brought in by EMS or police present differently from other patients. These preliminary findings could lead to a refinement in the data collection and form the basis for more definitive studies. A larger patient base study would provide more robust information of different populations. A prospective study of psychiatric patients could be valuable to better understand which are using the EMS system and why this means of transportation is chosen. It would be interesting to examine different EMS systems to determine whether reasons for transport and use of restraint vary by location. The findings could have significant ramifications for EMS planning and training. National EMS physicians, in their position statement on patient restraint, describe the need for protocols that address the indications for restraints and the type of patient restraint.5 Cheney and colleagues10 found similar results where 71% of restrained patients were alcohol or drug intoxicated. These findings could also have implications for training and alerting ED staff that psychiatric patients brought in by EMS or police present differently than the majority of psychiatric patients that are walk-ins or are brought by family members.



This study was limited in that the research was performed by one institution in an inner city emergency department. Since the study was retrospective, it was difficult to assess some of the details that would aid in understanding the reasons some patients come via EMS versus other means. It is uncertain why it was difficult to assess the number of injuries secondary to transporting patients in this study. The problem could be related to the low number of injuries, non-reporting of injuries, or retrospective nature of the study.



This study found that the EMS system is frequently used to transport intoxicated patients who do not have a regular psychiatrist, have an admitting diagnosis of drug use, and are later discharged from the ED. These findings could be used to alert ED staff that the psychiatric patient brought in by EMS or police present differently than the majority of psychiatric patients who walk in or are brought by family members. This information could be used further to develop a treatment protocol to assist the ED staff addressing the needs of these patients.  PP



1.    Kunen S, Niederhauser R, Smith PO, Morris JA, Marx BD. Race disparities in psychiatric rates in emergency departments. J Consult Clin Psychol. 2005;73(1):116-126.
2.    Pajonk FG, Schmitt P, Biedler A, et. al. Psychiatric emergencies in prehospital emergency medical systems: a prospective comparison of two urban settings. Gen Hosp Psychiatry. 2008;30(4):360-366.
3.    Grange J, Corbett, S. Violence against emergency medical service personnel. Prehosp Emerg Care. 2002;6(2):186-90.
4.    Tintinalli J. Violent patients and the prehospital providers. Ann Emerg Med. 1993;22(8):1276-1279.
5.    The National Association of EMS physicians policy statement. Available at: www.naemsp.org/pdef/restraints.pdf. Accessed June 29 2010.
6.    Cheney P Haddock T, Sanchez L. Safety and compliance with an emergency medical service direct psychiatric center transport protocols. Am J Emerg Med. 2008; 26(7):750-756.
7.    The National Association of EMS Physicians and National Association of State EMS directors in their 2002 report. Available at: www.naemsp.org/pdef/restraints.pdf. Accessed June 29 2010.
8.    Flannery R. Precipitants to psychiatric patient assaults: review of findings 2004-2006 with implications for the EMS and other health care providers. Int J Emerg Ment Health. 2007;9(1):5-11.
9.    Sankaranaraynan J, Puumala S. Epidemiology and characteristics of emergency department visits by US adults with psychiatric disorders and antipsychotic mention from 2000-2004. Curr Med Res Opin. 2007;23(6):1375-1385.
10.   Cheney PR, Gossett L, Fullerton-Gleason L, Weiss SJ, Ernst AA, Sklar D. Relationship of restraint use, patient injury, and assauls on EMS personnel. Prehosp Emerg Care. 2006;10(2):207-212.
11.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000.


Dr. Prowler is assistant instructor and Dr. Baldassano is assistant professor in the Department of Psychiatry at the Hospital of the University of Pennsylvania in Philadelphia.

Disclosures: Dr. Prowler reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Baldassano receives honoraria from Pfizer.

Off-label disclosure: This article includes discussion of pramipexole as an unapproved/experimental medication for the treatment of bipolar disorder.

Please direct all correspondence to: Matthew L. Prowler, MD, Assistant Instructor, Department of Psychiatry, Hospital of the University of Pennsylvania, 3440 Market St, Suite 200, Philadelphia, PA 19104-4399; Tel: 215-590-1119; Fax: 215-590-7350; E-mail: PROWLERM@email.chop.edu.



Pramipexole, a novel dopamine agonist, is approved for Parkinson’s disease and restless legs syndrome. Recent work has shown that pramipexole can provide a beneficial role in bipolar depression. To date, however, there has been no study of this compound for use in rapid cycling bipolar disorder. Cases of pramipexole augmentation in rapid cyclers with an active depressive episode are presented. A positive response with symptom reduction and without cycle induction or acceleration was observed. Possible mechanisms of this effect are considered. These findings suggest that pramipexole warrants more study in the treatment of affective disorders of varying illness courses.

Focus Points

• According to clinical support, pramipexole, a dopamine-3 receptor agonist, plays a beneficial role in bipolar depression.
• Patients who demonstrate a “rapid cycling” variant of bipolar disorder may experience increased depression severity and more overall time in a depressed phase compared to non-rapid cycling bipolar patients.
• Augmentation with this novel dopamine agonist may prove to be a safe and effective treatment approach for patients who demonstrate more extreme patterns of mood cycling.



The phenomenology and validity of rapid cycling bipolar disorder remains a topic of debate in the literature. Rapid cycling has been conceptualized as a dimensional course specifier on a continuum of mood episodes (necessitating ≥4 episodes of mood disturbance in 1 year in a patient with a diagnosis of bipolar I or II). Whether or not rapid cycling represents a distinct etiologic variant of bipolar disorder remains unclear.1,2 While there are data to support the use of mood stabilizers and atypical antipsychotics for the treatment of rapid cycling, this effect has been predominantly observed in the manic phase of the disease course.3 However, rapid cyclers more often present in a depressed phase of illness and may also demonstrate increased depression severity when compared to non-rapid cycling bipolar patients.4,5

Pramipexole, a dopamine agonist with preferential affinity for the dopamine (D)3 receptor, is approved for Parkinson’s disease and restless legs syndrome (RLS). Emerging evidence from two pilot studies6,7 shows that pramipexole can provide a beneficial role in bipolar depression. To date there has been no study of this compound for use in rapid cycling bipolar disorder. The authors present cases in which a positive response to pramipexole in rapid cyclers, with active depression phase predominance, has been observed.

These patients were evaluated and treated prospectively in the Hospital of the University of Pennsylvania Outpatient Bipolar Disorders Clinic. Diagnoses of bipolar disorder with rapid cycling were based on thorough initial evaluations and institution developed forms that follow the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision.8


Case Reports

Case 1

Mr. C is a 46-year-old single white male with a 20-year history of bipolar I and rapid cycling, who presented with a severe depressive episode of 6 month duration, and three previous and distinct, but less severe, depressive episodes within the past 12 months. His symptoms included depressed mood, decreased sleep with difficulty falling asleep, anhedonia, diminished energy, poor concentration, and decreased appetite resulting in a 7-pound weight loss. Suicidal ideation was not present. Mr. C’s medications included lithium 1,200 mg/day with a level of 1.1 mEq/l, carbamazepine with a level of 9.3 mg/l, and quetiapine 300 mg/day. This medication regimen had been helpful in reducing his cycling from 6–8 episodes to 3–4 episodes per year. For this current episode of depression, Mr. C had failed a therapeutic trial of lamotrigine up to 300 mg/day, aripiprazole augmentation up to 10 mg/day, olanzapine-fluoxetine combination up to 5/50 mg dose, and citalopram 60 mg/day. Pramipexole was added to his lithium/carbamazepine/quetiapine combination. The pramipexole was titrated slowly with an initial dose of .125 mg/day and increased every 3 days by .125 mg to a total dose of 2.5 mg/day. Mr. C responded rapidly to the pramipexole and began to feel significant improvement by day 12. By week 4, Mr. C reported improved mood with normal sleep, appetite, self-esteem, energy, and concentration. By week 12, Mr. C was in full remission of his depressive episode and his mood was considered euthymic. Side effects reported from pramipexole augmentation included mild nausea, which dissipated after 2 weeks of treatment, and sleepiness, which was mild and attenuated by taking at bedtime. After 1 year, Mr. C remains on pramipexole, lithium, and quetiapine. Carbamazepine was successfully tapered to discontinuation. His mood remains stable without evidence of rapid cycling.


Case 2

Ms. H is a 24-year-old single white female college student with bipolar I, rapid cycling, who experienced her first depressive episode at 15 years of age. Ms. H had four hospitalizations for mania and had been refractory to, or intolerant of, the following medications: carbamazepine, divalproex, olanzapine, aripiprazole, risperidal, quetiapine, and most antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors. Ms. H had spent significantly more time manic than depressed since illness onset, and reported three to four hypomanic or manic episodes in the past year (prior to this presenting episode). Ms. H’s mania responded to a combination of ziprasidone 320 mg/day, lithium 900 mg/day, and clonazepam 3 mg/day. She remained stable for 6 months on this regimen; however, she developed a severe depressive episode, which included low mood, poor sleep with frequent mid-cycle awakenings, low energy, diminished concentration, and passive suicidal ideation. Given her history of poor response to multiple conventional agents, pramipexole was initiated at .125 mg/day and titrated by .125 mg every 4 days. Ms. H began to show improvement in her depressive symptoms by day 5, which continued to remission of her depressive symptoms by 1 month of treatment at pramipexole 2.75 mg/day. Three months post-remission, Ms. H reported sub-syndromal depressive symptoms. The pramipexole was gradually raised to 3.5 mg/day but Ms. H began to have elevated energy and racing thoughts. Due to concerns of emerging hypomania, pramipexole was reduced to 3 mg/day with subsequent resolution of hypomanic symptoms. Her mood remains stable on 3 mg/day without any significant side effects.


Case 3

Mr. L is a 48-year-old divorced white male with a 12-year history of bipolar I disorder, rapid cycling, who presented with 4 weeks of worsening depressive symptoms in the context of a refractory disease course. His first episode of depression at 35 years of age was treated with paroxetine. In the third week of the SSRI trial, at a dose 30 mg, Mr. L reported a sudden increase in energy, grandiosity, irritability, and impulsive behavior. Despite SSRI discontinuation, Mr. L reported a progression of mood episodes, ~8–10 episodes/year, and  depression “more than 50% of the time.” Mr. L had one hospitalization for bipolar depression associated with suicidal ideation, and was refractory to trials of carbamazepine, divalproex, olanzapine, risperidone, and quetiapine, as well as >16 sessions of bilateral electroconvulsive therapy. At the time of evaluation for the index episode of depression, Mr. L was taking lamotrigine 300 mg/day, lithium carbonate 900 mg/day, aripiprazole 20 mg/day, and liothyronine sodium 50 mcg/day. He reported hopelessness, anhedonia, low energy, and poor sleep, and scored a 28 on the Beck Depression Inventory (BDI). No suicidality was present. Thyroid hormone was discontinued and pramipexole was initiated at a dose of .125 mg/day and titrated every 4 days by .125 mg to a total dose of 1.5 mg/day. At 3 months, Mr. L reported full remission of depressive symptoms, no cycling, and no side effects to the pramipexole. At 6 months, he reported stable mood with a BDI of 6.



In these three cases, the introduction of pramipexole was temporally related to the reduction or remission of depressive symptoms in rapid cycling bipolar patients. Effective doses were 1.5–3.0 mg, which is comparable to therapeutic doses that have been utilized for the treatment of Parkinson’s disease.9 At a higher dose, there were signs of emergent hypomania in one patient, which resolved with dose reduction. Pramipexole was otherwise well tolerated with side effects including mild nausea and fatigue. The positive effects from pramipexole augmentation appeared to be durable, lasting from 6 months to 1 year in these cases. While significant clinical improvement was observed in each case, ideally, it would have been beneficial to compare responses by means of standardized ratings. In each case, pramipexole was augmented to an existing regimen that included three psychotropic medications, perhaps reflecting the challenge of treating rapid cycling bipolar disorder as well as the refractory nature of these patients’ diseases. While polypharmacy may confound a clinical picture, it is notable that a positive response was appreciated with pramipexole introduction despite discrepant concomitant agents.

The role of dopamine agonists is evolving in the treatment of affective disorders. This practice is supported by a small, but promising, database (Table).6,7,10-12 While monoamine depletion studies have yielded inconsistent findings over the years, numerous reports using animal stress models have suggested that hypoactivity or decreased responsiveness of the mesolimbic dopamine pathway may be associated with, or mediate, concurrent depressed states.13 Further, potentiation of dopamine receptors has been forwarded as a final pathway mechanism of antidepressants.14 These findings were then clinically reinforced by two randomized controlled trials6,7 using pramipexole augmentation in depressed bipolar patients.

Other factors are worth consideration. Pramipexole, like antidepressants, has a suppressive effect on rapid eye movement (REM) sleep. In patients with RLS, pramipexole increased REM sleep latency (interval from sleep onset to first REM phase) and decreased total REM sleep time.15 Past work has found decreased REM latency in patients with depression.16-18 Thase and colleagues19 reported more frequent REM sleep abnormalities, including increased REM phase sleep, in patients with recurrent depression compared to a single episode. While findings from unipolar depression may not correlate to those of bipolar disorder, it is noteworthy that physiologic changes in sleep architecture, which pramipexole may affect therapeutically, are more pronounced in states of extreme affective cyclicity.

Furthermore, the D3 receptor, for which pramipexole has a high affinity, is densely distributed in the mesolimbic system. This region has been implicated in the anhedonic and motoric symptoms of depression.20 Pramipexole is also thought to have neurotrophic effects, which are mediated by the anti-apoptotic protein, bcl-2. This is the same mechanism for proposed neuroprotection seen with lithium and valproic acid.15

One concern in the use of dopamine agonists for bipolar disorder has been the risk of manic switch induction. The pramipexole trial by Zarate and colleagues6 found a hypomanic switch in one patient in the study group, which was fewer than those appreciated in the placebo group. A study by Leverich and colleagues21 examined manic switch rates in bipolar depression and augmentation with venlafaxine, sertraline, and bupropion versus placebo. Bupropion, the predominantly dopaminergic agent, conferred the lowest risk of switch to a hypomanic or manic state.

The risk of induction or acceleration of cycling is another consideration in the use of an agent such as pramipexole when treating depression in the context of rapid cycling. Previous studies have shown that antidepressants are risk factors for inducing cycling in bipolar patients with a history of rapid cycling.22 Since pramipexole is evincing antidepressant effects in two pilot studies6,7 as well as in the three cases presented in this article, one is prudent to raise a similar concern. For these patients that demonstrated a baseline rapid cycling pattern, pramipexole augmentation did not induce or accelerate cyclicity. This remains an important question that warrants study in a larger cohort.

This series builds on the findings of earlier studies to suggest that pramipexole is a promising pharmacologic agent that deserves more study in the treatment of affective disorders of varying illness courses. PP



1.   Kupka RW, Luckenbaugh DA, Post RM, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients. Am J Psychiatry. 2005;162(7):1273-1280.
2.   Maj M, Magliano L, Pirozzi R, Marasco C, Guarneri M. Validity of rapid cycling as a course specifier for bipolar disorder. Am J Psychiatry. 1994;151(7):1015-1019.
3.   Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry. 2006;67(suppl 11):22-27.
4.   Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program. Am J Psychiatry. 2004;161(10):1902-1908.
5.   Calabrese JR, Shelton MD, Bowden CL, et al. Bipolar rapid cycling: focus on depression as its hallmark. J Clin Psychiatry. 2001;62(suppl 14):34-41.
6.   Zarate CA Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56(1):54-60.
7.   Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161(3):564-566.
8.   Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
9.   Biglan KM, Holloway RG. A review of pramipexole and its clinical utility in Parkinson’s disease. Expert Opin Pharmacother. 2002;3(2):197-210.
10. Lattanzi L, et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord. 2002;4(5):307-314.
11. Sporn L, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review.  Ann Clin Psychiatry. 2000;12(3):137-140.
12. Gupta S, et al. Pramipexole: augmentation in the treatment of depressive symptoms. CNS Spectr. 2006;11(3):172-175.
13. Nestler EJ & Carlezon WA. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59(12):1151-1159.
14. Meyer JH, Krüger S, Wilson AA, et al. Lower dopamine transporter binding potential in striatum during depression. Neuroreport. 2001;12(18):4121-4125.
15. Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry. 2007;68(8):1230-1236.
16. Kupfer DJ, Foster FG. Interval between onset of sleep and rapid-eye movement sleep as an indicator of depression. Lancet. 1972;2(7779):684-686.
17. Foster FG, Kupfer DJ, Coble P, McPartland RJ. Rapid eye movement sleep density. An objective indicator in severe medical-depressive syndromes. Arch Gen Psychiatry. 1976;33(9):1119-1123.
18. Riemann D, Berger M, Voderholzer U. Sleep and depression–results from psychobiological studies: an overview. Biol Psychol. 2001;57(1-3):67-103.
19. Thase ME, Kupfer DJ, Buysse DJ, et al. Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: I. Comparison during acute depressive states. Biol Psychiatry. 1995;38(8):506-515.
20. Stein DJ. Depression, anhedonia, and psychomotor symptoms: the role of dopaminergic neurocircuitry. CNS Spectr. 2008;13(7):561-565.
21. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(2):232-239.
22. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377.


Dr. Ng is Medical Director of Psychiatric Emergency Services at Acadia Hospital in Bangor, Maine. Dr. Zeller is Chief of Psychiatric Emergency Services at Alameda County Medical Center in Oakland, California. Dr. Rhoades is a medical writer in Steamboat Springs, Colorado.

Disclosure: Dr. Ng has served as a consultant to Alexza Pharmaceuticals. Dr. Zeller is on the speakers’ bureaus of Eli Lilly and Pfizer and is a consultant to Alexza Pharmaceuticals. Dr. Rhoades is a paid consultant to Alexza Pharmaceuticals.

Off-label disclosure: This article includes discussion of unapproved/investigational treatments for agitation.

Please direct all correspondence to: Anthony T. Ng, MD, FAPA, Medical Director, Psychiatric Emergency Services, Acadia Hospital, 268 Stillwater Ave, Bangor, Maine 04401; Tel: 207-973-6345;  Fax: 207-973-7328; E-mail: atng@emh.org.



Agitation, characterized by motor restlessness and accompanying mental tension that may escalate into violence, is a serious behavioral emergency encountered often in the emergency setting. Behavioral intervention (eg, verbal de-escalation, seclusion) should be the initial approach for management of agitated patients, but when these techniques are ineffective, pharmacologic treatment becomes necessary. This article reviews the clinical challenges in managing agitation in the emergency setting. An ideal agent for the acute treatment of agitated patients should be easy to administer and not traumatic; provide tranquilization without excessive sedation that may interfere with patient interaction, diagnosis, and selection of additional therapy; have a rapid onset of action and a sufficient duration of action to allow for transport of patients to appropriate services; and have low risk for significant adverse reactions and drug interactions. Currently available pharmacologic treatments for agitation do not fulfill all of these criteria, and there are significant unmet needs for novel antiagitation treatments that are rapid in onset, accepted by patients and staff, less invasive (as compared with intramuscular or intravenous formulations), and easy and safe to administer.


Focus Points

• Agitation demands rapid treatment that frequently precludes a thorough evaluation of etiology, therefore requiring rapidly acting treatments that are effective and safe.
• While nonpharmacologic intervention should be attempted whenever possible, medication may be administered voluntarily or under duress, with the aim of safely and swiftly making the patient less agitated and hostile.
• There are significant unmet needs for novel antiagitation treatments that are rapid in onset, accepted by patients and staff, less invasive (as compared with intramuscular or intravenous formulations), and easy and safe to administer.



Agitation in adults is a psychiatric/medical emergency that requires rapid and effective intervention to avoid harm to patients, their families, other individuals receiving care in the emergency setting, and healthcare professionals. Ineffectively managed agitation can also greatly increase the overall cost of patient treatment and create additional expenses that may result from injury and time lost from work.

Agitation is characterized by excessive motor or verbal activity, which may include irritability, uncooperativeness, threatening gestures, and assault.1,2 It is a common clinical challenge in the emergency setting that may lead to violent, destructive behavior and cause extreme personal distress, while posing a physical risk to the patient, caregivers, nursing staff, and others.3 As many as 1.7 million medical emergency room visits per year may involve agitated patients,4 and 20% to 50% of emergency psychiatry visits in the United States may involve patients who are at risk for agitation.4,5 Approximately 10% of patients encountered in emergency psychiatry settings may become agitated or violent during assessment.6

Schizophrenia and bipolar disorder are very common causes of agitation for individuals who present in the emergency department.5,7,8 Patients with psychoses result in ~900,000 emergency department visits annually.5 Schizophrenia is disproportionately common among homeless people, with an incidence of 27%, which contributes to their high frequency of presentation with agitation in the emergency department.7 It is important to note that agitation among patients with schizophrenia or bipolar disorder may be precipitated or exacerbated by both patient-related factors (eg, male, younger age, history of substance abuse, poor adherence to antipsychotics, history of physically aggressive behavior,9-12 and the characteristics of the environment in which they are managed (eg, an overcrowded emergency department).13 Unpremeditated violence in patients with agitation is often preceded by a prodromal period of 30–60 minutes, during which they may exhibit increased pacing or loud speech.14 Recognizing these prodromal symptoms provides an opportunity for early de-escalation and/or offering pharmacologic treatment.

Several tools have been developed to assist in the identification of patients who are likely to become violent in different treatment settings. The Brøset Violence Checklist (BVC) measures confusion, irritability, boisterousness, physical threats, verbal threats, and attacks on objects with each scored for its presence (1) or absence (0). The sum of scores is then totaled with a total score of 0, suggesting that the risk of violence is small; scores 1 and 2 suggest that the risk of violence is moderate, and preventive measures should be taken; and scores ≥3 indicate that the risk of violence is very high and that action should be taken.15 The Historical, Clinical, and Risk Management Violence Risk Assessment Scheme is a 20-item scale that gathers information about past history of violence, current clinical status, and environmental/support factors that may increase risk for violence.16 It has been shown to be useful for the clinical psychiatric, forensic, and correctional settings.16 A third tool that may be useful for prediction of violence in the emergency department is the McNeil-Binder Checklist, which evaluates history of physical attacks or fear-inducing behavior within 2 weeks, absence of suicidal behavior, schizophrenic or manic diagnosis, male gender, and currently married or living together status, to predict violent behavior. It has been shown to have a sensitivity of 57.2% and a specificity of 70.0% for prediction of violence in psychiatric inpatients.17 None of these prediction tools have been evaluated in the emergency department and all but the BVC require at least some information about the patient’s history.

The occurrence of agitation and violence significantly impacts the agitated individual, other patients around him or her, and healthcare personnel.18 Results from one survey of psychiatric emergency services in the US indicated that agitation resulted in an average of 8 patient-to-staff assaults per facility each year.19 Most of these episodes caused injuries to personnel that were sufficiently severe to result in absences from work.19 Results from one study20 of violence in the emergency department indicated that 80% of respondents reported that at least one staff member had been injured by a violent patient in the preceding 5 years, and 43% reported physical attacks on staff at least once per month. Results from another survey21 of 106 emergency department personnel indicated that 57% were physically assaulted, 48% reported impaired job performance for the rest of the shift or the rest of the week after an incident of violence, 73% were afraid of patients as a result of violence, and 25% took days off because of violence.

The symptoms of agitation may be very similar across a wide range of diagnoses, including medical conditions, toxicity, and psychiatric illness (Table 1).22-27 The terms used to define agitation typically include increased psychomotor activity; aggression; disinhibition/impulsivity; and irritable, anxious, or labile mood.28 Numerous different definitions for agitation have been put forward in the medical literature, and they vary based on the condition (eg, dementia, traumatic brain injury, schizophrenia, bipolar disorder) believed to underlie patients’ symptoms.28 It has been suggested that the lack of a uniform and precise definition of agitation may contribute to misrecognition (both over- and underrecognition) of this condition and misdetermination of its causes in the acute care setting.28

The etiology of agitation is not completely understood, but it is believed that abnormalities in the biogenic amines—serotonin, dopamine, and norepinephrine—as well as the inhibitory neurotransmitter g-aminobutyric acid (GABA) are all involved.29-31 It has been suggested that agitation associated with psychosis, mania, and substance abuse may be correlated with elevated dopaminergic neurotransmission, and that decreased GABAergic transmission is characteristic of agitation associated with dementia, depression, and anxiety.32

Agitation demands rapid treatment that frequently precludes a thorough evaluation of etiology. Clinicians therefore require rapidly acting treatments that are effective and safe, regardless of the genesis of agitation. It is important to note that treatment requirements and unmet needs for the management of patients with agitation vary from one setting to another and that those in the emergency department are very different from those for a patient presenting to a psychiatric clinic.33-36 The etiology of agitation for the patient in the emergency department may be unknown, while some patient history is likely to be available to personnel in the psychiatric clinic. Treatment selection may be more difficult in the emergency department versus the psychiatric clinic because healthcare professionals in the psychiatric clinic may have more information about efficacy of prior treatments in a given patient.


Acute Management of The Agitated Patient

Diagnosis and establishment of the acute treatment plan for the agitated patient is difficult because of the immediate need for intervention, which may increase diagnostic difficulty.

Establishment of a provisional diagnosis is a crucial step in the management of the agitated patient, and medical causes of agitation and substance abuse should be ruled out, if possible, before assuming a psychiatric etiology. Patient characteristics that increase the probability of a non-psychiatric cause of agitation include lack of prior psychiatric history, older age, and new or pre-existing medical complaints.37,38 It has been suggested that a brief medical work-up be carried out in patients without a psychiatric history, with features not consistent with a psychiatric diagnosis (eg, lethargy, confusion), with abnormal vital signs, with sudden onset of agitation, and who are known to have recently started any new medications (eg, anticholinergics, steroids).39

Ideally, initial intervention in the agitated patient should be as nonrestrictive as possible. Techniques such as verbal de-escalation (“talking the patient down”) or destimulation (placing the patient in a quiet room ) are effective in some agitated individuals and should be attempted prior to more forceful interventions.14,40

While nonpharmacologic intervention should be attempted whenever possible as a first step in the acute management of agitated patients, it is often ineffective in some individuals who present in the emergency setting.18 Rapid and safe tranquilization of aggressive/violent patients is often necessary; medication may be given voluntarily or under duress, with the aim of safely and swiftly making the patient less agitated and hostile. It should be noted that offering the agitated patient medication can go hand-in-hand with non-restrictive interventions such as verbal de-escalation and providing the patient with an opportunity for time in a quiet environment.41 Involuntary administration of medication should be considered coercive in the same sense as forced seclusion or restraint.

The goal of acute pharmacologic treatment for agitation is to calm the patient while avoiding excessive sedation that can interfere with the ability to continue the psychiatric evaluation and intervention.42,43 Excessive sedation that results in a requirement for continuous observation and/or assistance with toileting also increases the burden on emergency department staff.36 Prompt administration of effective medications to the agitated patient has the potential to reduce the probability of harm to self or others, permit accomplishment of needed diagnostic tests, attenuate psychosis, and reduce the requirement for restraint.36

The choice of medication for a patient with agitation should be guided by the etiology underlying the episode if it is known. For example, agitation resulting from organic causes (eg, hypoglycemia, hypoxia, thyroid storm) should not be treated with an antipsychotic, while administration of an antipsychotic and/or benzodiazepine is appropriate for agitation that has a psychiatric etiology.39 The remainder of this article focuses on treatment of agitated patients using antipsychotics and benzodiazepines.

Current drugs used for the acute treatment of agitation may be administered orally, intravenously (IV), or by injections into the muscle (intramuscular [IM]).44 Each of these routes of delivery may have important limitations. Administration of an oral agent may not be possible in a very agitated patient and this route of administration often results in a slow onset of action.44 Intravenous administration of medications may result in a very rapid onset of action, but establishing an IV line may be very difficult and potentially dangerous in the agitated patient. In addition, IV administration of some medications used to treat agitation may result in cardiac and/or respiratory complications.44 Results from one study45 have shown further that IM administration of haloperidol did not result in more rapid resolution of agitation than delivery of an oral concentrate. Similarly, comparison of the combination of oral risperidone and oral lorazepam versus IM haloperidol plus IM lorazepam in patients with agitation indicated no significant between-treatment differences in onset of action.46 Nevertheless, IM drug administration generally achieves therapeutic concentrations more rapidly than oral delivery.47 A recent systematic review48 of clinical trials focused on the acute treatment of agitation indicated generally more rapid onset of action for IM versus oral administration of the same agents.

Intramuscular injections are easier to administer than IV infusions, and some patients will agree to this route of delivery for medications to more rapidly control their agitation. However, the onset of action with IM injection of a given medication may be slower and the pharmacologic effects more variable than those observed after IV administration of the same drug.49,50 For example, the onset of action with midazolam for calming agitated patients is 1–5 minutes for IV delivery versus 18 minutes for IM administration.51,52 Additionally, the pain associated with IM injection may be poorly tolerated by some patients.44 Any intervention that is aversive to the patient, particularly if it is administered involuntarily, may be viewed as punishment and has the potential to impair the physician-patient relationship and effective longer-term management after resolution of the episode of agitation.42 Further, approaching the patient with a needle may increase stress for both patients and their families and escalate agitation.53 Both IV and IM administration of medications to the agitated patient are also associated with the risk for needle-stick injuries to emergency department staff.54 Despite these limitations, the relatively rapid onset of action for IM and IV administration of antipsychotics and/or benzodiazepines is an important advantage when the behavior of an agitated patient poses an imminent risk to himself and others, and parenteral drug administration is the only feasible treatment alternative.

The characteristics of an ideal medication for the acute management of agitated patients have been set forth by several investigators (Table 2).55,56 They include easy preparation by staff and nontraumatic administration (no needles) with no associated pain or requirement for restraint; rapid onset of action with little interpatient variability in pharmacokinetics and pharmacodynamics; sufficient duration of effect for transport of patients to appropriate services; tranquilization without excessive sedation that may interfere with patient interaction, diagnosis, and selection of additional therapy; and low risk for significant adverse reactions and drug interactions.55,56



Guidelines for Acute Management of Agitation in the Emergency Setting

Several guidelines for the acute management of agitated patients have been published; those from the Joint Commission on Accreditation of Healthcare Organizations as well as the Centers for Medicare and Medicaid Services indicate that nonphysical forms of behavior management (eg, verbal intervention or show of force) are the appropriate first-line strategy. If medication is required, the use of oral drugs rather than IM preparations is recommended.57 The Expert Consensus Panel for Behavioral Emergencies consensus regarding the acute management of agitated patients in the emergency department setting differs somewhat from these guidelines. This consensus, based on responses to a survey completed by 48 experts in the acute management of agitated patients, indicated that first-line oral options for the acute treatment of agitation associated with schizophrenia are olanzapine alone, risperidone alone or combined with a benzodiazepine, and haloperidol plus a benzodiazepine. Parenteral agents supported by experts included IM olanzapine and IM ziprasidone. The experts recommended initial use of benzodiazepines when no information was available about the patient’s condition, when there was no specific treatment available for the patient’s condition, or when the patient was intoxicated. Haloperidol was viewed as being as effective as any currently available antipsychotic, and it was recommended that it should be administered alone or with a benzodiazepine unless the patient is medically compromised.42 While these expert recommendations provide guidance for optimal use of existing medications for the acute treatment of agitated patient, none of the currently recommended approaches meets all of the criteria for an ideal treatment set forth above (Table 2).33-35,55,56


Limitations of Current Pharmacologic Treatment Options

Oral Drug Administration

Oral agents, particularly atypical or second-generation antipsychotics, have been used extensively for the acute treatment of agitation,36 but they may be limited by slow onset of action.58 Results from controlled clinical trials indicate that the shortest onset of action for oral olanzapine or haloperidol in patients experiencing an episode of agitation is ~1 hour.59 The combinations of oral risperidone and lorazepam or haloperidol and lorazepam have been reported to have onsets of action of 30 minutes in patients with agitation.60 Another potential limitation of oral medications is patients “cheeking” (taking, but not swallowing) oral tablets.55

While not specifically approved for the treatment of agitation, orally disintegrating formulations of several antipsychotics (eg, risperidone, olanzapine, aripiprazole) have been developed.59,61,62 This formulation may facilitate antipsychotic delivery to agitated patients, particular those who might not comply with treatment, but their pharmacokinetic profiles, including time to maximum plasma concentration, are equivalent to those for conventional tablets.61,63,64


Intramuscular Injection

Intramuscular administration of conventional or atypical antipsychotics provides more rapid onset of action than oral delivery, but may be associated with higher risk for adverse events and patient objections. Intramuscular ziprasidone has been shown to have an onset of action of ~30 minutes in agitated patients in one study.65 Intramuscular olanzapine is also rapidly absorbed and produces significant reductions in agitation within 30 minutes, but has been associated with significant reductions in systolic and diastolic blood pressure and pulse rate.66,67

Objection to IM injection may create a barrier to this approach to acute treatment of agitation in many patients. Results from one survey indicated that patients most preferred pills or capsules, followed by liquid medication, and then “an injection I agree to.”56 Physicians are also concerned that injected medication will compromise the physician-patient relationship.55


Excessive Sedation

While tranquilizing or calming the agitated patient is the central aim of pharmacotherapy, avoiding excessive sedation that may interfere with further evaluation and treatment is now also recognized as an important aspect of intervention. Heavy sedation of patients may help to ensure the safety of both patients and staff, but it also makes it difficult or impossible to elicit useful information from them.3 Review of randomized clinical trial data indicated that oral ziprasidone and quetiapine (not approved for treatment of agitation) and IM olanzapine have higher dose-related sedative potential while oral risperidone (not approved for treatment of agitation) and IM aripiprazole have lower sedative potential.68 However, other studies have suggested that IM olanzapine may have low risk for sedation in the acute treatment setting.69,70

While the risk with IM administration of antipsychotics for excessive sedation that may interfere with further patient evaluation and intervention appears to be lower than that after oral delivery,36,55 results from several studies have indicated that IM formulations of some atypical antipsychotics do have at least some liability for excessive sedation. In contrast to the conclusions from Cañas,68 results from a study28 comparing IM aripiprazole and IM lorazepam indicated excessive sedation (Agitation-Calmness Evaluation Scale score of 8 or 9) during the initial 2 hours after first injection in 17.3% and 19.1% of aripiprazole- and lorazepam-treated patients, respectively. Parenterally administered benzodiazepines have also been associated with excessive sedation.71 The combination of these drugs with a conventional or atypical antipsychotic may further increase the risk for excessive sedation versus treatment with single agents.


Other Adverse Events Associated with Current Acute Treatments for Agitation

All agents currently used for the acute treatment of agitation have the potential for clinically important adverse events. Conventional antipsychotics (eg, haloperidol) may produce dysphoria, dystonia, and akathisia (in up to 33% of patients), as well as postural hypotension leading to syncope, and possible cardiac events. In addition to being aversive to patients, the symptoms of akathisia may be confused with the underlying agitation.36 This has the potential to lead to inappropriate increases in drug dosing. Conventional neuroleptics (eg, haloperidol) often require the use of concomitant anticholinergics to prevent or treat extrapyramidal symptoms, and administration of these drugs can lead to cognitive disturbances. Treatment with conventional neuroleptics may also lead to neuroleptic malignant syndrome, particularly when administered in high doses to agitated patients.72 Acute dystonic reactions, which may be life threatening, have been reported to occur in 9% of agitated patients treated with haloperidol.73 Due in large part to these limitations, the use of conventional antipsychotics is no longer considered “best practice” for any of the major conditions contributing to agitation.55,74

Administration of atypical antipsychotics may also result in significant adverse events when used in the acute care setting. Treatment with olanzapine may lead to bradycardia, orthostatic hypotension, and increased somnolence when administered with lorazepam.55 Risperidone may be associated with the development of extrapyramidal symptoms.75 Ziprasidone may produce nausea, headache, dizziness, and possible risk for QTc prolongation.55 Quetiapine may result in orthostatic hypotension.76 Aripiprazole may produce nausea and vomiting.77

Medications used for the acute treatment of agitation also have the potential for clinically significant drug-drug interactions; this is especially important in patients with comorbid medical conditions. Lorazepam has a substantial potential for interactions with prescription drugs, drugs of abuse, and alcohol.78 Haloperidol, ziprasidone, aripiprazole, and quetiapine are all metabolized, at least partially, by cytochrome P450 (CYP) 3A4 and may interact with agents that induce or inhibit this enzyme, including carbamazepine, valproate, phenytoin, phenobarbital, rifampicin, quinidine, glucocorticoids, and macrolide antibiotics.79-81 Olanzapine is metabolized by CYP 2D6 and 1A2, and it may interact with fluvoxamine, fluoxetine, sertraline, and grapefruit juice.79,80 Risperidone is partially metabolized by CYP 2D6, but has little risk for clinically significant drug interactions.79,80


New Alternatives for Acute Treatment of The Agitated Patient

While conventional or atypical antipsychotics, used alone or in combination with a benzodiazepine, have been shown to be effective for the acute treatment of agitation, the results summarized in the preceding sections indicate that there is a clear need for new options for the initial pharmacologic management of the agitated patient who presents in the emergency setting. The magnitude of this need is clearly reflected by survey results indicating that 8.5% of patients who present with agitation require restraint during psychiatric emergency visits,56 suggesting that current approaches to treatment are far from optimal for rapidly calming these individuals.

Asenapine sublingual tablets are a new option for the treatment of acute episodes of schizophrenia and for treatment of acute manic or mixed episodes of bipolar I disorder. Bioavailability is 35% when taken sublingually, but <2% if ingested.81 This formulation might be expected to have a rapid onset of action and be suitable for treatment of patients with agitation. An inhaled formulation of loxapine (AZ-004; inhaled loxapine), which penetrates deeply into the lungs, has also been shown to be effective for reducing agitation, as measured by Positive and Negative Syndrome Scale–Excited Component scores in patients with schizophrenia and bipolar disorder with an onset of action <10 minutes.82



Agitated individuals present often in the emergency care setting, and prompt and effective management of these patients is an important priority. A wide range of options has been employed in the acute treatment of agitation, but many have important limitations, including slow onset of action, excessive sedation, requirement of parenteral administration, and risk for potentially serious side effects and drug interactions. No currently available single agent or combination matches the characteristics of an ideal acute intervention for agitation, which include being easy to administer and not traumatic; rapid onset of action and a sufficient duration of action to allow for transport of patients to appropriate services; provision of tranquilization without excessive sedation that may interfere with patient interaction, diagnosis, and selection of additional therapy; and low risk for significant adverse reactions and drug interactions. Further study of alternative therapies for acute agitation that address some or all of these limitations is required. PP



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