CNS Spectr. 2010;15:7(Suppl 8):10-13
Funding for this activity has been provided by an educational grant from Lilly USA, LLC.
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Faculty Disclosure Policy Statement
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.
Statement of Need and Purpose
Although considerable progress has been made in schizophrenia management, challenges remain. The treatment of schizophrenia is complicated by medical and psychiatric comorbidities and different treatment stages, resulting in frequent polypharmacy and potential side effect/adverse event risks including significant weight gain. Schizophrenia is associated with increased medical comorbidity likely caused by interactions between lifestyle, environment, and the disease itself. The Clinical Antipsychotic Trials of Intervention Effectiveness data indicated that a large number of schizophrenia patients met metabolic syndrome criteria at baseline and that few were receiving treatment for metabolic-related conditions: rates of nontreatment were 30.2% for diabetes, 62.4% for hypertension, and 88% for dyslipidemia.
At the completion of this activity, participants should be better able to:
• Identify the long-term health impact of common psychiatric and medical comorbidities in patients with schizophrenia
• Assess current evidence on the efficacy, safety, and tolerability of treatments for schizophrenia that address comorbid psychiatric and medical conditions to create targeted care plans
• Integrate psychoeducation, establish a clinician-patient alliance to provide a supportive care environment, and address real world clinical concerns
This activity is designed to meet the educational needs of psychiatrists.
Faculty Affiliations and Disclosures
Leslie Citrome, MD, MPH, is professor in the Department of Psychiatry at New York University School of Medicine in New York City, and director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York. Dr. Citrome has received research support from AstraZeneca, Eli Lilly, Janssen, and Pfizer; is a consultant and advisor to Azur, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, and Pfizer; has received compensation for services on the advisory boards of Eli Lilly, Janssen, Merck, Novartis, and Pfizer; has received honoraria for lectures, papers, and teaching from AstraZeneca, Azur, Eli Lilly, Merck, Novartis, and Pfizer; has received consulting fees from Azur, GlaxoSmithKline, and Janssen; and owns stock in Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer.
Oliver Freudenreich, MD, is assistant professor of psychiatry at Harvard Medical School in Cambridge, Massachusetts, and director of the First Episode and Early Psychosis program at Massachusetts General Hospital in Boston. Dr. Freudenreich has received research support from Pfizer, honoraria from Reed Medical Education, and consulting fees from Beacon Health Strategies.
Peter J. Weiden, MD, is professor of psychiatry and director of the Psychotic Disorders program at the University of Illinois in Chicago. Dr. P.J. Weiden is a consultant to AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, Forest, Merck, Novartis, Ortho-McNeil-Janssen, Pfizer, Takeda, Vanda, and Wyeth; has received grant support from the National Institute of Mental Health and Ortho-McNeil-Janssen; and is a speaker for Novartis, Ortho-McNeil-Janssen, and Pfizer.
Michael Weiden, MD, is associate professor of pulmonary and critical care medicine at the New York University School of Medicine in New York. Dr. M. Weiden reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
CME Course Director James C.-Y. Chou, MD, is associate professor of psychiatry at Mount Sinai School of Medicine in New York City. Dr. Chou has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, and Pfizer.
Margaret McNamara McClure, PhD, is assistant professor of psychiatry, and director of the Advanced Psychology Fellowship at Mount Sinai School of Medicine in New York City. Dr. McNamara McClure reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Activity Review Information
The activity content has been peer reviewed by Margaret McNamara McClure, PhD.
Review Date: May 14, 2010.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding visit www.lillygrantoffice.com.
To Receive Credit for this Activity
Read this Expert Panel Supplement, reflect on the information presented, and complete the CME posttest and evaluation on pages 14 and 15. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by July 1, 2012 to be eligible for credit.
Release date: July 31, 2010
Termination date: July 31, 2012
The estimated time to complete this activity is 2 hours.
CME Podcast Version
A related audio CME PsychCastTM will also be available online at: cmepsychcast.mblcommunications.com and via the “Science & Medicine” section of iTunes.
Dr. P.J. Weiden is professor of psychiatry and director of the Psychotic Disorders Program at the University of Illinois in Chicago. Dr. M. Weiden is associate professor of pulmonary and critical care medicine at the New York University School of Medicine in New York.
Disclosures: Dr. P.J. Weiden is a consultant to AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, Forest, Ortho-McNeil-Janssen, Merck, Novartis, Pfizer, Takeda, Vanda, and Wyeth; has received grant support from the National Institute of Mental Health and Ortho-McNeil-Janssen; and is a speaker for Novartis, Ortho-McNeil-Janssen, and Pfizer. Dr. M. Weiden reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Mr. A is 24 years of age with a history of schizophrenia (Slide 1). He has been living with his parents and has been ill for a few years. Police saw him on the street in a state of crisis and brought him to the emergency room (ER). He was very anxious and his delusions of being in great physical danger had worsened. He reported a history of asthma, but it was noted that his asthma occurred a long time ago and was inactive; however, due to his anxiety, his smoking had increased to where it was continuous. At the time he was brought to the ER, Mr. A was triaged to psychiatry and became agitated in the waiting area; hence, security was called. He was about to be restrained and given an intramuscular dose (IM) of lorazepam, but the psychiatrist noted that he was having trouble breathing and stopped the IM before it was given. The psychiatrist noticed that Mr. A was wheezing, had a rapid respiratory rate of 25/minute, was tachycardic, and sweating. His pulse oximeter measurement was 90% saturated, which is considered low.
Mr. A was re-interviewed and reported that he previously had asthma. His parents were contacted and agreed that he had active asthma, had stopped his psychiatric treatment several months ago, and, more recently, stopped his asthma medications when his prescriptions were not refilled ~1 week prior to this episode. An emergency arterial blood gas showed a pH of acidosis at 7.27; a Po2 of 60 (normal is 80); and a Pco2 of 48 (normal is 40). The Pco2 was of particular concern because if he was retaining CO2, respiratory failure was imminent.
He was admitted to an intensive care unit for an acute asthma attack. He was intubated and recovered fairly rapidly. After he recovered on antipsychotics and returned to taking his asthma medication, he was transferred to a psychiatric unit. Due to his poor adherence to antipsychotics, the treatment plan was to start him on a long-acting injectable antipsychotic to help monitor his adherence.
Mr. A’s case illustrates the relationship between acute asthma and an acute psychotic episode presenting in a patient with schizophrenia. There is a lot of concern regarding obesity, cardiovascular risk factors, and hyperlipidemia in patients with schizophrenia, but respiratory problems are also very prominent and can also demand our attention.
Even at the first presentation of schizophrenia, patients are at risk for pulmonary problems. At first episode in a study using a matched control design, significant differences in pulmonary function tests were found.1 Intuitively, it would seem that smoking, unemployment, and other nonspecific risk factors would be the cause; however, even when those are statistically adjusted for, patients with schizophrenia have poor respiratory functioning. Pulmonary function tests would not reveal this clinically; however, due to the link between the central nervous system (CNS) and breathing and respiration, the slightest changes in respiratory functioning may add to some background symptoms of panic and anxiety in any disorder. The CNS control of ventilation is highly complex with primary centers being located in multiple nuclei in the brain stem, medulla, and pons. As expected for such a vital physiological function, there are multiple and redundant brain structures that control respiration. The sensorimotor cortex, orbital frontal cortex, limbic lobe, amygdala, and hypothalamus are intimately involved in ventilation. Many of these centers (eg, limbic system, amygdala, and hypothalamus) are also closely associated with regulation of mood and thought. It is not surprising, then, that there are reciprocal and interconnected interactions between respiration and emotional states.
Psychosis Is Associated With Excess Mortality From Asthma
Asthma is defined as a reversible obstruction to airflow that responds to treatment with β-agonists. This disease is rising in incidence and can be lethal. Fortunately, appropriate treatment is effective in reducing both morbidity and mortality from asthma. The most common psychiatric comorbidities with asthma are affective disorder, panic, and anxiety disorders1-3; but these psychiatric comorbidities do not seem to lead to increased risk for dying from asthma, whereas comorbid schizophrenia does significantly add to the risk for lethal asthma.4-6 It appears that exacerbation of psychotic symptoms is especially worrisome for patients who also suffer from asthma. There is no conclusive epidemiologic evidence that there is an excess of asthma diagnosis among schizophrenia patients, or vice versa. However, when these diagnoses do coexist, there are significant increases in asthma-related morbidity2 and mortality, probably due to the enormous challenges of access to, and compliance with, asthma treatment.
Asthma and schizophrenia are both common illnesses, so any busy psychiatric program will see patients with both disorders. Mr. A’s case illustrates a few important points about asthma and the mechanism in which normal asthma can become lethal asthma.
Asthma literature reveals the risk factors for patients with asthma that lead to death, or what the predictors are in asthma and lethal asthma for poor outcome. First, having psychosis is a risk factor for asthma-induced mortality, and it may come as a surprise that this is not replicated for patients with depression or anxiety. Evidently, psychosis, presumably schizophrenia, may put someone at a higher risk for asthma-induced mortality.
What is the relationship between antipsychotics and asthma-induced mortality? Do antipsychotics increase the risk for a severe asthma attack? When patients who have died due to asthma or have had serious asthma undergo a psychological or a pharmacologic autopsy, a recent history of stopping antipsychotics in the last few months is somewhere between 2–5 times what is expected.3
It seems that when patients stop their antipsychotic medication they become more psychotic, which is a vicious interaction (Slide 2). In turn, when patients become psychotic and stop taking their asthma medication, they do not report this to their physicians. The stress of the psychosis can induce severe asthma attacks, but they are too psychotic to seek help; hence, they will present later in the course of their asthma attack. Mr. A’s case shows the various parts of this cycle. He stopped taking his antipsychotic before he stopped taking his asthma medication. He then presented to the ER in fairly late-stage asthma, but it was his schizophrenia that was noted first and his asthma second, and it only was late in the evaluation that the seriousness of the asthma attack was noted. Fortunately for Mr. A, he did survive the attack, but it illustrates the cycle of how medical comorbidities interact with medication adherence and psychosis, and often it is the psychiatric problem that will set off the cascade.
Higher Mortality From Asthma in Schizophrenia: Findings From A Case Control Study
A history of antipsychotic treatment, but not antidepressant treatment, increases the risk for sudden death from asthma. A well-designed, case-controlled study compared 131 cases of fatal asthma with 3,930 non-fatal asthma controls identified by case records and pharmacy data from the Canadian province of Saskatchewan.3 In this study, 7% of asthma deaths were in patients with histories of antipsychotic treatment compared to 3.8% of controls (OR=1.88; P<.05). Further analysis of the association between antipsychotics and increased risk for death revealed that those at excess risk were patients who had stopped their antipsychotic within 2 months of their death.3 Slide 3 shows thAt asthmatic patients on antipsychotics are not at greater risk when they are on medication but at greater risk when they have stopped. In contrast to antipsychotics, there was no signal of increased risk from either taking or stopping sedatives, suggesting that this is specific to antipsychotic efficacy. This finding suggests, but does not prove, that the problem is not any direct risk for antipsychotics. Rather, the underlying risk factor appears to be some combination of psychotic relapse, lack of access to care, or a domino effect of noncompliance with antiasthma medications following soon after stopping the antipsychotic.
Mr. B is 39 years of age, with a history of schizoaffective disorder who was considered a “revolving-door” patient (Slide 4). He had some comorbidities with prior marijuana and alcohol use. Mr. B presented to the ER on a Thursday, with a fairly characteristic relapse. He was given the standard protocol, a “cocktail” that consisted of a single injection of haloperidol 5 mg IM; benztropine 2 mg IM; and lorazepam 1 mg IM. He received two of these injections and later that evening was admitted to an inpatient unit. On Friday, he was started on oral haloperidol, and on Friday evening, after everyone left, he started showing signs of strid Or and respiratory distress. He made the sign for choking and began to turn blue. The on-call resident made a provisional diagnosis of laryngeal dystonia, and the code team was called for an incipient respiratory arrest. In the meantime, he was given benztropine IM stat, and ~15 minutes later his respiratory symptoms abated completely.
At this point, he was started on standing lorazepam and was switched to another antipsychotic that was less likely to cause acute dystonia. Mr. B’s IM PRN, which had been haloperidol, was changed to a newer medication less likely to cause dystonia.
Risk Factors for Laryngospasm
The case of Mr. B also represents an acute emergency admission, but his pulmonary or respiratory event occurred many hours later. Mr. B illustrates how an acute dystonic reaction can present as respiratory arrest in the form of a laryngeal dystonia.8-12 Since Mr. B is at risk for for laryngospasm, there are some medication-related risk factors, patient-related risk factors, and some service risk factors, which are also very important. His pharmacologic risk factor was due to recent IM exposure to a conventional, high potency antipsychotic. There is a greater risk with an IM than with a PO because of the pharmacokinetics where a rapid rise in plasma level of the antipsychotic after an IM injection. There will be higher plasma levels occuring relatively quickly, and the risk of dystonia is not just a function of plasma level, but how quickly it increases over time. Rapid increases in plasma levels are more likely to cause acute dystonic reactions than a slower, gradual increase.
His PRN had included benztropine, and while that may prevent the dystonia from happening in the ER, the patient becomes at risk for having a dystonic reaction when the benztropine dissipates. There may be a rebound phenomenon since dystonia is more likely to happen when anticholinergics are discontinued. The same is also true for benzodiazepines. Benzodiazepines are less well known to be effective in the acute treatment of dystonia but can be as effective as anticholinergics for acute dystonia; however, discontinuation may put patients at higher risk.
In looking at demographic risk factors, Mr. B was somewhat older, but in general, children and adolescents are generally at a higher risk for side effects. Mr. B was at risk because he was male and African American. Parenthetically, age is the reason that prochlorperazine is contraindicated in children; several deaths were related to laryngospasm in children who used prochlorperazine for nausea.
In the case of Mr. B, there were service risk factors. There was poor communication between services. The inpatient unit did not know that he received haloperidol IM. There is also a lack of staff training in recognition of various forms of antipsychotic-induced extrapyramidal symptoms (EPS). Fortunately for the patient, the resident on call that evening was able to recognize Mr. B’s signs and symptoms as possible dystonia.
EPS and Dystonia
Acute dystonic reactions often happen in the beginning of treatment when the patient is acutely ill. The staff may not know the patient, and the patient may not be a good historian. The overlap between behavioral manifestations of dystonia and psychiatric symptoms may also confuse the diagnostic picture; hence, there may be a real problem with the patient’s credibility or staff awareness of that particular patient’s pathology in that the report of dystonia may be mistaken to be part of the psychopathology (Slide 5).13 The delay between medication exposure and onset of dystonia can be many hours. Acute dystonia is likely to be intermittent, meaning that it is possible for physicians not to witness dystonia, thereby relying on self-report, which may be unreliable.
These two case vignettes illustrated how interactions between schizophrenia, antipsychotics, and respiratory problems can interrelate in very serious ways. There are some general suggestions about matching antipsychotics with patients who have known vulnerabilities such as asthma, COPD, or obstructive sleep apnea, or those who have had histories of dystonia or dyskinesia (Slide 6). While it is beyond the scope of this discussion to cover all of the common respiratory comorbidities, it is possible to match certain characteristics of antipsychotic medications with specific adverse event profiles to patients with specific comorbidities. For example, patients with obstructive sleep apnea generally get worse with weight gain, so antipsychotics that tend to cause weight gain are problematic in this comorbid condition.
If a patient has a respiratory problem that involves hypoventilation or sleep apnea, one would want to avoid more sedating medications that suppress breathing during the evening in general. There is no specific medication that worsens asthma. If there is a history of severe dystonia or respiratory problems related to neurologic side effects, clearly one is going to move toward medications that have less EPS liability. It is important for physicians to know that antipsychotics actually decrease mortality from asthma; therefore, compliance needs to be considered in any way obtained. In the end, effective antipsychotic treatment will promote adherence to other medications, including that for asthma, decreasing risk for morbidity and mortality.
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