Vol. 10 No.

2 February 1995

Journal of Pain and Symptom Management 131

Neuropsychiatric Syndromes and Psychological Symptoms in Patients with Advanced Cancer
William Breitbart, MD, Eduardo Bruera, MD, Harvey Chochinov, MD, and Mary Lynch, MD Memorial Sloan-Kettering Cancer Center (W.B.), New York, New York; and Edmonton General Hospital (E.B.), Edmonton, Alberta; Manitoba Treatment and Research Foundation (H. C.), Winnipeg; and Victoria GeneralHospital (M.L.), Halifax, Nova Scotia, Canada

Abstract This article represents the contributions of the panel on "NeuropsychiatricSyndromes and Psychological Symptoms" of the National Cancer Institute of Canada Workshop on Symptom Control and Supportive Care in Patients with Advanced Cancer. The panel's presentations focused on mood disorders and cognitive disorders, and described the current state of knowledge regarding prevalence, assessment, and intervention. Recommendations f or future research are presented based on a consensus of the panel as to the need tofiU glaring gaps in our current state of knowledge, and a desire to improve the quality of research in this area of paUiative medicine. Recommendations for future research on neuropsychiatric symptoms and syndromes in palliative care include (1) adoption of uniform terminology (taxonomy of disorders) and diagnostic classification systems, (2) utilization of existing validated tools and measures in prevalence and intervention research, (3) development of new tools and measures that are more applicable and relevant to the palliative care setting, (4) encouragementfor studies of the prevalence of neuropsychiatric symptoms and syndromes, (5) promotion of intervention studies utilizing pharvnacologic and nonpharmacologic treatmentsfor depressive disorders and cognitive disorders in advanced cancer patients, and (6) expansion of the focus of such research to other neuropsychiatric disorders (for example, anxiety disorders, posttraumatic stress disorders, and sleep disorders), symptoms (fatigue and tension) and related issues (suicidal ideation and desire for hastened death). J Pain Symptom Manage 1995:10;131-141. Key Words Palliative care, advanced cancer, neuropsychiatric syndromes, psychological symptoms, depression, cognitive disorders

Introduction
The National Cancer Institute of Canada Workshop on Symptom Control and Supportive Care in Patients with Advanced Cancer, which took place on October 28-29, 1993, included an afternoon session on "NeuropsyAddress reprint requests to: William Breitbart, MD, Memorial Sloan-Kettering Cancer Center, Box 421, 1275 York Avenue, New York, NY 10021, USA. Acceptedfor publication:June 20, 1994.
© U.S.

chiatric Syndromes and Psychological Symptoms in Patients with Advanced Cancer." The panel of presenters included Drs. Mary Lynch, William Breitbart, Harvey Chochinov, and Eduardo Bruera, all experts in the area of neuropsychiatric symptom control in the advanced cancer patient. The presentations themselves were divided into three sections: mood disorders (depression), cognitive disorders (delirium), and pharmacotherapies (interventions). The presentations all included a review of the current state of knowledge
0885-3924/95/$9.50

CancerPain ReliefCommittee, 1995 Published by Elsevier,NewYork,NewYork

SSDI 0885-3924(94)00075-V

and (d) neuropsychiatric disturbance studies should be approached on two levels. .'~. one must first distinguish between symptoms and syndromes. Highlighted in the presentations and the discussions following were inadequately developed areas of research. The DSM-III-R (soon to be DSM-1V) classification system for psychiatric disorders is the most widely used diagnostic system in North America. cognitive impairment disorders. These problems present a general obstacle to the study of depression in advanced cancer patients.:~-16 T h e broad variation in the reported prevalence of depression is due to the problems of terminology. Utilization of the different diagnostic classification systems. such as m o o d disorders (depression). Several of the studies on the prevalence of depression examine levels of severity of depressive symptoms (often as r e p o r t e d by patients on self-report measures such as the Beck Depression Inventory) and do not reflect rates of diagnosis of the specific clinical syndrome of major depression (although they may be highly correlated). and Research Diagnostic Criteria (RDC). 1. 5-15 Only a limited n u m b e r of these studies e x a m i n e d prevalence of depression in cancer patients with far-advanced disease. DSM. and the paucity of clinical research to date in the areas of assessment and treatment or intervention. and suicidal ideation. methodologic problems impeding progress of research. and strategies for overcoming obstacles to research on neuropsychiatric syndromes and symptoms in the palliative care setting. 10 No. The following general statements reflect the panel's and the greater workshop participants' consensus about the relevance of this area of research in the care of the advanced cancer patient: (a) Symptom control and supportive care should be priorities for research in the care of patients with advanced cancer. criteria for a diagnosis of major depressive syndrome. A critical problem associated with diagnosing depression in patients with cancer lies with the issue of how best to interpret the physical/ somatic symptoms of depression. insomnia.5% to 58% based on psychiatric consultation database studies 1-4 and research based prevalence studies. The symptom of sadness or depressed m o o d is not equivalent to the synd r o m e of major depression. Table 1 lists the Diagnostic and Statistical M a n u a l of Mental Disorders. Kathol and colleagues 1:~found as much as a 13% difference in rates of major depression when utilizing criteria of the DSMIII (38%).1~t5 and these suggest that depression is more c o m m o n in later stages of cancer. third edition. DSM-III-R (29%). and (3) they must be understood in the context of the patient and family as the unit of concern. assessment. anxiety. in cancer pafients. (2) they cannot be studied in isolation. Mood Disorders Presentations and discussions in this section focused primarily on the syndrome of major depression.III-R. and pharmacotherapies. and the application of diagnostic systems not originally intended for use in medically ill populations. that is. Specific recommendations for future research focus in this area were made and are described here. Prevalence rates for major depressive syndromes in cancer patients range from 4. Vol. (b) symptoms and syndromes of a neuropsychiatric nature. Distinguishing between normal sadness and the syndrome of major depression in advanced cancer patients has important treatment implications. both as symptoms and as syndromes or disorders whenever possible. methodology. Reports also suggest that depression is associated with increased morbidity. the significant associated morbidity. The evidence presented by the panel speaks to the high prevalence of neuropsychiatric syndromes and symptoms in the advanced cancer patient. 2 February 1995 regarding prevalence. revised 17 (DSM-III-R). is often leads to widely varying rates of detection of depression in cancer patients. and RDC (25%). ranging in prevalence from 23% to 58%. To diminish these problems. DSM-III.7. (c) neuropsychiatric symptoms and syndromes must be understood in the following contexts: (1) they coexist with multiple other physical and psychological symptoms and interact with them. cognitive disorders. The following is a brief re~4ew of the panel's presentations on mood disorders. have an important place in any agenda that focuses on symptom control in the advanced cancer patient.132 Breitbart et al. and treatment of neuropsychiatric syndromes and symptoms (focusing on depression and delirium) in the advanced cancer patient.

Syndromes and Advanced Cancer 133 Table 1 DSM-III-R Criteria for Major Depressive Syndrome At least five of the following symptoms have been persistent for 2 weeks or more: 1. ''z7 Cognitive disorders.2% for m a j o r depression a n d 3. dysphoria. bDesigned for use with DSM-IIIcriteria. a n d delirium in particular..t h r e s h o l d E n d i c o t t criteria. pessimism 4. Delirium has b e e n d e f i n e d as "a transient organic brain s y n d r o m e c h a r a c t e r i z e d by the acute onset of d i s o r d e r e d attention a n d cognition.t h e clinician attempts to d e t e r m i n e if the physical s y m p t o m is d u e to c a n c e r illness o r t r e a t m e n t (and so does n o t include it) or d u e to a depressive d i s o r d e r (in which case it is i n c l u d e d as a criterion s y m p t o m ) . Psychological/cognitive symptoms:worthlessness/guilt. a n d (d) a substitutive a p p r o a c h . identical prevalence rates o f 9. i n c l u d i n g diagnostic classification systems. Cognitive Disorders Presentations a n d discussions in this section f o c u s e d primarily on the s y n d r o m e o f delirium. or fatigue or loss of energy 3. or anhedonia (at least one symptom must be from this group) 2 Physical/somatic symptoms: sleep disorder. Delirium is highly prevalent in c a n c e r patients with a d v a n c e d disease. F o u r different a p p r o a c h e s to the diagnosis o f m a j o r depression in the c a n c e r patient have b e e n describedlg. appetite or weight change. Additionally. indecisiveness/poor concentration. (c) an etiologic a p p r o a c h . a c c o m p a n i e d by disturbances o f psychom o t o r b e h a v i o r a n d perception.w h e r e physical s y m p t o m s of uncertain etiology are r e p l a c e d by o t h e r n o n s o m a t i c symptoms.d e l e t e s a n d disregards all physical s y m p t o m s f r o m consideration. have e n o r m o u s relevance to s y m p t o m c o n t r o l a n d supportive care. Depressed mood. with prevalence Table 3 Endicott Substitution Criteria Physical/somatic symptom 1. Fatigue. Social withdrawal. Diminished ability to think or concentrate. or thoughts of death/suicidal ideation Adapted from reference 17.VoL 10 No. decreased talkativeness 3.2°: (a) an inclusive app r o a c h . particularly in the last weeks o f life. 2 February 1995 Neuropsychiatric . few studies o f depression in terminally ill or a d v a n c e d c a n c e r patients have used such research assessment m e t h o d s to date. U n f o r t u n a t e l y .. Change in appetite. Interestingly. loss of interest or pleasure. (b) an exclusive a p p r o a c h . Table 3 lists a n u m b e r o f available assessment m e t h o d s for depression. f u r t h e r work is necessary in a d a p t i n g to the limitations o f such m e t h o d s in their application to p o p u l a t i o n s with a d v a n c e d cancer. Sleep disturbance Psychological symptom substitute 1. s t r u c t u r e d diagnostic interviews. valid a n d reliable. as well as E n d i c o t t substitution criteria. Brooding. Tearfulness.8% for m i n o r depression (total = 13%) were f o u n d utilizing RDC high t h r e s h o l d criteria a n d h i g h . 3. Lack of reactivity Research Assessment Methods for Depression in Cancer Patients Diagnostic classification systems Diagnostic and Statistical Manual DSM-III. a n d s c r e e n i n g instruments. IV~7 Endicott Substitution Criteria 21 Research Diagnostic Criteria is (RDC) Structured diagnostic interviews Schedule for Affective and Schizophrenia ~s (SADS)" Diagnostic Interview Schedule 22 (DIS) b Structured Clinical Interview for DSM-III-R2:~ (SCID) Screening instruments--self-report General Health Questionnaire-30 ~4 (GHQ) Hospital Anxiety and Depression Scale 25 (HADS) Beck Depression Inventoryz6 (BDI) "Designed for use with RDC criteria. 21 listed in Table 2 a n d utilized in studies by Kathol a n d colleagues l~ a n d C h o c h i n o v and colleagues. T h e latter a p p r o a c h is best exemplified by the E n d i c o t t Substitution Criteria.i n c l u d e s all s y m p t o m s w h e t h e r or n o t they may be s e c o n d a r y to c a n c e r illness or treatment. Research assessment m e t h o d s for depressive disorders in c a n c e r patients have b e c o m e m o r e sophisticated. depressed appearance 2. self-pit). n o t allowing t h e m to c o n t r i b u t e to a diagnosis o f m a j o r depressive s y n d r o m e . loss of energy 4. weight 2.. indecisiveness . 14 C h o c h i n o v a n d colleagues J4 studied the prevalence o f depression in a terminally ill c a n c e r Table 2 p o p u l a t i o n a n d c o m p a r e d low versus high diagnostic thresholds. III-R.

General cognitive impairment 1. Both the DSM and ICD systems are being revised again. Amnestic disorder due to a general medical condition b. Prevalence of delirium ranged from 38% to 9% with DSM-III criteria being most inclusive (38%).83 294.00 293. Substance-induced persisting dementia e. not otherwise specified rates ranging from 25% t o 8 5 % .%. anxiety. It is anticipated that the DSM-IV classification system for cognitive impairment disorders will replace DSM-III-R as the dominant diagnostic system in North America. and the ICD-10 research criteria being least inclusive (9%). Substance-induced delirium c. 28-35 Delirium is associated with increased morbidity in the terminally ill. which is the most widely used system in North America. Dementia of the Alzheimer's type b.80 310. "Associated with physical disorders or conditions. In DSM.10 294. such as pain. or whose etiology is unknown. uniform terminology or diagnostic classification systems. Dementia due to multiple etiologies f. Dementia a. Multiple terms are often used to refer to similar cognitive disorders: delirium. and delusional disorders will be relocated and included in the major diagnostic groups.49 diagnostic classification system. bNOS.134 Breitbart et al. . organic brain syndrome. including infection. Amnestic disorder not otherwise specified C. with ICD-10 and DSM-IV systems due to appear shortly. 41-46 Unfortunately.80 Delirium Dementia Amnestic disorder Organic delusional disorder Organic hallucinosis Organic m o o d disorder Organic anxiety disorder Organic personality disorder Organic mental disorder (NOS) b Adapted IYom reference 51. DSM-III-R. and staff.81 293. It is an area underresearched in palliative medicine."which are listed and described in Table 5. Delirium a. 38-4° in later stages of illness. personality. causing distress in patients. Vol. Often a preterminal event.IV. Specific cognitive impairment 1. family members.00 294. and ICD-10 research criteria. Dementia not otherwise specified B. 2 February 1995 Table 4 DSM-IIIoR Classification O r g a n i c Mental D i s o r d e r s ~ 293.82 293. Dementia due to other medical conditions d. and rare paraneoplastic syndromes. encephalopathy. Substance-induced persisting amnestic disorder c. Liptzin and colleagues 5° assessed 325 elderly patients admitted to a general hospital with three different diagnostic criteria sets to determine the presence of delirium: DSM-III. reversible dementia. Vascular dementia c. Delirium not otherwise specified 2. delirium has multiple etiologies in the advanced cancer patient. and organic mental disorder. Clinical case studies or research reports that utilize various or idiosyncratic terminologies are less helpful contributions to the literature than those that use standard.10 294.:~7Delirium can interfere dramatically with the recognition and control of other physical and psychological symptoms. :¢4. 10 No. chemotherapy and other medication side effects (including opioids). organ failure. delirium is underrecognized and undertreated. Cognitive disorder not otherwise specified Adapted fi'om reference 51. Diagnostic classification systems for cognitive disorders relevant to palliative medicine also includes the DSM-II147 which is the version that preceded DSM-III-R but is the basis of a n u m b e r of research diagnostic tools and the current International Classification of Diseases (ICD-9. Table 5 Proposed DSM-IV Cognitive Impairment Disorders A. The "organic" mood. acute confusional states. Amnestic disorders a. DSM-III-R being somewhat less inclusive (33%). Table 4 lists the types of organic mental disorders described in the DSM-III-R classification system. Delirium due to multiple etiologies d. and listed as secondary disorders. The use of a uniform diagnostic classification system would increase the consistency and reliability of both prevalence and intervention studies in the area of delirium and other cognitive disorders.51 the "organic mental disorders" are being eliminated and replaced by "cognitive impairment disorders. In an empirical study of diagnostic criteria for delirium. ICD-10) 48. Impediments to progress in treatment and research in delirium have included confusion regarding terminology and lack of consistency in utilizing diagnostic classification systems. Delirium due to a general medical condition b. cognitive failure.

74have b e e n studied a n d shown effective in c o n t r o l l e d trials. Antipsychotic n e u r o l e p t i c drugs ( d o p a m i n e . or RDC diagnoses o f m a j o r depression. or evolving dementia.b l o c k i n g drugs).00 Delirium due to a general medical condition A. 52-62 O n l y a limited n u m b e r o f studies o f cognitive i m p a i r m e n t disorders in palliative care settings have utilized such research assessm e n t methods. or perceptual disturbance) that is not better accounted for by a preexisting. perceptual disturbances. sustain. or shift attention. disorientation. but only 0 . Disturbance of consciousness (that is. Table 6 lists the DSM-IV criteria for delirium T h e essential features o f acute onset o f d i s o r d e r e d attention a n d cognition are retained. 65. O f the two controlled trials in the terminally ill populations. reduced clarity of awareness of the environment) with reduced ability to focus.72 nortriptyline.2 % o f hospitalized c a n c e r patients receive haloperidol for the m a n a g e m e n t o f the s y m p t o m s related to deliriumfi :~. or laboratory findings of a general medical conditionjudged to be etiologically related to the disturbance. T h e r e are few c o n t r o l l e d studies o f antidepressant d r u g t r e a t m e n t for depressive disorders in c a n c e r patients in general a n d even fewer that focus o n the terminally ill. Change in cognition (such as memory deficit. DSM-III-R. only 1 % . o r anxiety. C. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 135 Table 6 Proposed DSM-IV Criteria for Delirium 293. established. There is evidencefrom the history. as m a n y as 17% receive an antipsychotic for agitation o r psychological distress. Research assessment m e t h o d s for delirium in a d v a n c e d c a n c e r patients are listed in Table 7. 5 % . reveal that antidepressants a n d antipsychotics are vastly u n d e r u s e d a n d that the majority o f patients with depression a n d delirium go untreated. D. The disturbance develops over a sort period of time (usually hours to days) and tends to fluctuate during the course of the day. MI o f these studies treated c a n c e r patients with depressive s y m p t o m s o f a certain t h r e s h o l d o f severity based o n observer-rated o r self-report measures o f depression. 71 mianserin 69. Adapted from retbrence 51. 67-74 To date. or delusions are no l o n g e r viewed as essential to the diagnosis o f delirium. 10 No. Associated p h e n o m e n a such as p s y c h o m o t o r behavioral changes. hallucinations. a n d a n o t h e r Table 7 Research Assessment Methods for Delirium in Cancer Patients Diagnostic classification systems DSM-III. distress. Several surveys o f psychotropic d r u g utilization in hospitalized c a n c e r patients. 63-66 Antidepressants are prescribed for the t r e a t m e n t o f depression in .64In terminally ill p o p u l a tions. are utilized frequently as antiemetics. a n d have b e e n reviewed extensively elsewhere.5 8 % .3 % o f hospitalized c a n c e r patients 6s. B. o n e study 7] o f nortriptyline was n o t c o m p l e t e d because o f high attrition rates d u e to d r u g side effects a n d disease progression.Vol. DSM-III-R. ICD-10 Diagnostic inter~fiews/instruments Delirium Symptom Interview54 (DSI) Confusion Assessment Method s5 (CAM) Delirimn rating scales Delirium Rating Scale 56 (DRS) Confusion Rating Scale 5v (CRS) Saskatoon Delirium Checklist 5s (SDC) Cognitive impairment screening instrument Mini-Mental State Exam 59 (MMSE) Short Portable Mental Status Questionnaire 6° (SPMSQ) Cognitive Capacity Screening Examination ~1 (CCSE) Blessed Orientation Memory Concentration Test62 (BOMC) Pharmacotherapies Presentations a n d discussions in this section focused primarily o n p h a r m a c o l o g i c interventions for the t r e a t m e n t o f m a j o r depressive syndromes a n d delirium.c'6 despite an estimated prevalence o f m a j o r depression in a d v a n c e d c a n c e r patients o f 2 3 % .7° a n d a l p r a z o l a m 7:~. i n c l u d i n g those with a d v a n c e d disease. physical examination. N o n e utilized s t r u c t u r e d diagnostic interviews to establish DSM-III. DSM-IV ICD-9. despite an estimated prevalence o f delirium r a n g i n g f r o m 25% in the hospitalized c a n c e r patient to 85% in the terminally ill.64 a n d u p to 5% o f terminally ill c a n c e r patients. language disturbance. i m i p r a m i n e . the essential nature o f delirium as a s y n d r o m e has b e e n maintained. Despite c h a n g e s in the classification o f organic m e n t a l disorders or cognitive impairm e n t disorders m a d e in the evolution f r o m DSM-III to DSM-III-R to DSM-1V. ~s.

and fluvoxamine). hospice) or the focus on patient comfort. Controlled trials of these newer agents for the t r e a t m e n t of depression in patients with advanced disease are necessary. Vol. sertraline. Often however. 10 No. Newer agents with fewer side effects and simplified dosage regimens. a n d mazindol) have b e e n shown to be effective antidepressants in cancer patients and other medically ill populations. Such supportive measures have not b e e n studied in terms of their impact on the symptoms of delirium.00 Amitriptyline Doxepin Imipramine Desipramine Nortriptyline Clomipramine Second-generation antidepressants Burpropion Trazodone Heterocyclic antidepressants Maprotiline . a n d m a n a g e m e n t of the symptoms of delirium. 2 February 1995 study of alprazolam 7:~ contained a sample of only 20 patients. measures to help reduce anxiety and disorientation. it is often irreversible or difficult to treat. symptomatic and supportive therapies are important. but few. these supportive techniques alone are not effective. Pemoline was also shown to be an effective antidepressant particularly useful for terminally ill patients. they may be the only steps taken. and symptomatic treatm e n t with neuroleptic or sedative medications are necessary (Table 9). versus the risk or benefit as they pertain to delirium. such as the serotonin-specific reuptake inhibitors (fluoxetine. and the reversible inhibitors of m o n o a m i n e oxidase subtype A (RIMA). methylphenidate. d e x t r o a m p h e t a m i n e .:~:~.5-150 0. A n u m b e r of psychotherapy-intervention trials for the treatm e n t of psychological distress and depression have b e e n c o n d u c t e d with cancer patients.:~5.:~. Fluid and electrolyte balance. Most often the etiology of terminal delirium is multifactorial or may not be determined. Haloperidol. :~j. nutrition.:~i T h e treatm e n t of delirium in the dying cancer patient is in fact unique and presents certain dilemmas. vitamins. Bruera and colleagues ss report that an etiology was discovered in less than 50% of terminally ill patients with cognitive failure. A debate is now ongoing as to the a p p r o p r i a t e extent of diagnostic evaluation Table 8 Antidepressant Medications Used in Advanced Cancer Patients Therapeutic daily Drug Tricyclic antidepressants dosage mg (oral) 25-125 25-125 25-125 25-125 25-125 25-125 200-450 150-300 50-75 100-150 20 50-200 10-50 50-300 20-40 30-60 20-40 100-600 5-30 5-30 37. 75 Bruera and colleagues 76 studied mazindol's effects on depression in terminally ill cancer patients utilizing a double-blind design.:~sMore research in this area is n e e d e d to help guide clinicians. W h e n a distinct cause is f o u n d for delirium in the terminally ill. if any. with no available oral route for drug administration. a neuroleptic drug that is a potent d o p a m i n e blocker. so that unpleasant or painful diagnostics may be avoided. a n d interactions with and education of family m e m b e r s may be useful. 77 Table 8 lists the currently available drugs useful in the treatm e n t of depression in cancer patients with advanced illness. pemoline. correction of those factors. who could utilize the chewable tablets for buccal absorption.:sS. Diagnostic workup in pursuit of an etiology for delirium may be limited by the setting (home. in the dying patient.136 Breitbart et al. 7s-:)7 A standard a p p r o a c h to the m a n a g e m e n t of delirium in the medically ill and in the cancer patient includes a search for underlying causes. paroxetine.:~s In fact. is the agent of choice in the t r e a t m e n t . In addition to seeking out and potentially correcting underlying causes for delirium. ~7. Psychostimulants (for example. 27.4anoxapine Serotonin-specific reuptake inhibitors Fluoxetine Sertraline Paroxetine Fluvoxamine Monoamine oxidase inhibitors Isocarboxazid Phenelzine Tranylcypromine Moclobemide Psychostimulants Dextroamphetamine Methylphenidate Pemoline Benzodiazepines Alprazolam Adapted frOlil reti_~rence4. have included patients with faradvanced disease.75-6. such as clorgyline (not yet available) and moclobemide. may have i m p o r t a n t applications in treating depression in patients with advanced cancer.:~1.

currently important topic is that of differential therapeutics.5 m g every 2 .0 m g every 1-4 h r PO. IV. of delirium in the medically ill. 3. if2 These new agents and newer antipsychotics that will become available in the near future may have important roles in managing delirium in the terminally ill. 27. and midazolam. IV. IM 3 0 .5-50 mg every 4-12 hr PO. Prevalence studies of neuropsychiatric syndromes and symptoms should be encouraged.1 0 0 m g every 24 h r IV.VoL I0 No. PO 0.I°8 T h e r e f o r e hypoactive and hyperactive deliria may require different treatment strategies. Iv. ill Newer antipsychotic agents are being developed that have more specific or no d o p a m i n e antagonist effects and fewer neurologic side effects (that is. or SC. PO.l°°-l°4 T h e r e are few controlled trials of neuroleptic agents in the m a n a g e m e n t of delirium or agitation due to organic mental disorders 1°1-1°4 and even fewer that have been conducted in terminally ill patients. 5 . a short acting benzodiazepine usually administered as continuous infusions for the m a n a g e m e n t of agitation and terminal delirium.. Several interesting clinical questions in this area exist. and staff?. 2. Specific recommendations include: 1. SC. extra pyramidal effects or tardive dyskinesia) such as clozaril or sulpiride. p h e n o m e n o l o g i e s and etiologies. SC Midazolam Parenteral doses are generally twice as potent as oral do~s. Recommendations are made with the intended goals of improving the quality of research in this area o f palliative medicine and a desire to fill glaring gaps in our current state of knowledge. Studies of neuropsychiatric symptoms/ syndromes should adopt the use of uniform terminology (taxonomy of disorders) and diagnostic classification systems wherever relevant and available. 0 . comparison trials of various agents or combinations of agents in the m a n a g e m e n t of delirium in the terminally ill are necessary. IM. a phenothiazine neuroleptic. What are effective pharmacologic and nonpharmacologic interventions? An interesting.l°5-J°7 More controlled.~5'ss. subcutaneous infusions a r e generally accepted modes of drug administration in the terminally ill. oral forms of medication are preferred. Of particular interest are studies in special palliative care populations (that is. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 137 Table 9 Medications for Managing Delirium in Advanced Cancer Patients Generic name Neuroleptics Haloperidol Thiorodazine Chlorpromazine Methotrimeprazine Benzodiazepines Lorazepam Approximate daily dosage range route. family. Existing validated tools and measures should be utilized in prevalence and intervention research in neuropsychiatric symptoms and syndromes (Tables 3 and 7). IM 12. Must we always treat delirium in the terminally ill or dying patient? What are appropriate goals for treatment? What is the impact of delirium on patients.9s It is often combined with a benzodiazepine drug such as lorazepam. need to be developed. intravenous bolus injections or infusions should be administered slowly.5-2. 31.s:~. 1°9 others suggest that hypoactive delirium may best respond to psychostimulants or combinations of neuroleptics and stimulant. Hypoactive and hyperactive subtypes of delirium have been described. 11° Stimulants may also play a role in the managem e n t of terminally ill patients with various cognitive impairment disorders experienced by patients on opioid infusions.. New tools and measures that are (a) more applicable and practical for use in the palliative care setting and (b) address symptoms and related issues where measures do not yet exist. 99 T h e palliative care/hospice literature also describes the use of methotrimeprazine. While some investigators suggest that neuroleptics may be equally effective for both subtypes of delirium. IM 10-75 mg every 4-8 hr PO 12. SC. and more research could helpfully inform clinical management. . IV.1 2 h r PO. 4. and seem to have distinct Specific Recommendations for Future Research Recommendations for future research in the area of neuropsychiatric syndromes and psychological symptoms are based on a consensus of the panel and workshop participants. intramuscular injections should be avoided if repeated use becomes necessaw.5-50 mg every 4-8 hr IV.

N o n p h a r m a c o l o g i c interventions alone or in combination with antidepressant drug treatments should be encouraged. Holland JC.21:382. Cancer 1978. Theis D.J Clin Oncol 1985.65:29-32. Noyes R. Simon MA. Proc R Soc Med 1972. m o r e controlled trials of antidepressant efficacy in the t r e a t m e n t of depression in advanced cancer patients are needed. 2 February 1995 elderly. hospice. Holland JC. terminally ill. 10 No. et al.147:8. Lizt MA. Mastrovita R. The cancer patient with pain: psychiatric complications and their management. Wells KB. T h e panel felt that prevalence and intervention studies were necessary in several areas affecting advanced cancer patients including (a) anxiety disorder. Williams J. Davies ADM. Lansky SB.20:432. Derogatis LR.43:243-254. 6. A prevalence study of depression in a cancer hospital population. Detection of depressive disorders for patients receiving pre-paid or fee-for. an SSRI and a psychostimulant) or novel uses of existing agents (that is. Med Clin North Am 1987. 13. Burnam A. Levine P. Diag- . Studies examining the pharmacokinetics and p h a r m a c o d y n a m i c s of antidepressant drugs in advanced cancer patients are necessary. Weddington W~. serotonin-specific reuptake inhibitors. 3.138 Breitbart et al. Clin Otolaryngol 1984.71:243-248. Depression in women treated for gynecological cancer: clinical and neuroendocrine assessment. 8. McCartney CF. The diagnosis of depression in hospitalized patients with cancer [abst C-587]. J Psychosom Res 1987. (b) posttraumatic stress disorders. Massie MJ. Am J Psychiatry 1986. Massie MJ. Expansion of the focus of research to other neuropsychiatric syndromes symptoms and related issues. and (e) suicidal ideation and desire for hastened death. Refe'rel'R2e$ 1. (c) newer antipsychotic agents as they b e c o m e available. et al. 11.262:3298-3302. Depression in hospitalized cancer patients. Dean C. Kathol RG. Morton RP. Clamon G. Gorzynski JG. medical m a n a g e m e n t alone versus drug intervention). 2. BukbergJB. Lander S. 1021-1024. or staff. controlled intervention trials in the treatment of delirium are n e e d e d that focus on (a) comparison of existing agents (haloperidol versus lozepam). children. Psychosom Med 1984. 143:447-452.service care. 10. 12. Mutgi A. Current and lifetime incidence of psychiatric disorders among a group of extremity sarcoma survivors. (b) combinations of agents (haloperidol and stimulant versus haloperidol alone). those receiving opioids. 6. 17. These might include medical interventions such as hydration or psychosocial interventions aimed at patients. (d) symptoms such as fatigue and tension. Lipowski ZJ.31:385-392. 'The prevalence of depression in the terminally ill: effects of diagnostic criteria and symptom threshold judgements. h o r m o n a l treatments such as testosterone). Enns M. Holland J. Segraves KB. HollandJC. Proc Am Assoc Cancer Res 1980. Vol. Comparative studies of psychological function in patients with advanced cancer: II. Absence of major depressive disorder in female cancer patients. 9. h o m e care. Herrman CA. Studies examining the efficacy for depression of psychostimulants. 4. and (d) n o n p h a r m a c o l o g i c interventions (that is. American Psychiatric Association (APA). et al.151:537-540. (c) sleep disorders. In depressive disorders. In cognitive i m p a i r m e n t disorders. 5. JAMA 1983. The prevalence of psychiatric disorders among cancer patients. Holland J.42:13851391. J Psychosom Res 1986. Intervention studies utilizing pharmacologic and n o n p h a r m a c o l o g i c treatments for neuropsychiatric syndromes and symptoms should be encouraged.9:181-185. Proc Am Soc Clin Oncol 1979. Penman D. Psychiatric morbidity following mastectomy: preoperative predictors and types of illness. Bukberg JB. 14. AmJ Psychiatry 1994. Morrow GR. Chochinov HM. Evans DL.3:1553-1560. Hinton J. Quality of life in treated head and neck cancer patients: a preliminary report. Interviewer-rated current and past psychological symptoms. et al. Psychiatric consultation in fatal illness. and settings (hospital. Mental disorders in cancer patients. et al. Silverfarb PM.30:121-125. Wilson KG.249:751-757. Hays RD. Diagnosis of major depression in cancer patients according to four sets of criteria. 15. Schmale A. and those with preexisting dementia). and other new agents that may be m o r e tolerable in advanced cancer patients are also needed. 5. T h e panel also wanted to encourage studies of depression treatment that utilized novel combinations of pharmacologic agents (that is.JAMA 1989. 16. T h e panel also felt that studies that focused on prevention of neuropsychiatric s y n d r o m e s / s y m p t o m s as well as studies of cost and impact on families and the health-care system should be encouraged. Psychosom Med 1981. and palliative care units). Plumb M. Am J Psychiatry 1990.46:199-212. 7. families.

Research diagnostic criteria. DSM-III.148:454-457. MacDonald RN. American Psychiatric Association (APA).39:13-16. Fogel B. New York. Rodin G. Use of methylphenidate as an adjuvant to narcotics for the treatment of cancer pain. Bruera E. Bruera E. Psychosocial Aspects Cancer 1990. Weaver S. In: Stoudemire A.R. Int Psychogeriatr 1991 . rationale and reliability. et al. Zigmond AS. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 139 nostic and statistical manual of mental disorders. Massie MJ. Delirium and other organic mental disorders in a general hospital. Measurement of depression in patients with cancer. Stiefel F. Current and emerging issues in cancer pain: researcher and practice. 19. The last 24 hr of life. J Palliat Care 1990. Bruera E. et al.71:67-70. Hanson J. 51. Corticosteroids in cancer: neuropsychiatric complications. McDermott W.3:333-336. Breitbart W. National institute of mental health diagnostic interview schedule. McCallionJ. 1994. Portenoy R. Gray G. J Pain Symptom Manage 1994.7:192-195. Foley KM. J Pain Symptom Manage 1991 .53:2243-2249. its history characteristics and validity. Helzer JE.258:1789-1792. Breitbart WS. Cleary P. 46. 26. 30. Miller L. Miller MJ. Craven J. World Health Organization (WHO). 34.Vol. 3rd ed rev. Mental disorders: glossary and guide to their classification in accordance with the 9th revision of the international classification of diseases. 47. et al. Liptzin B. . et al. Holland JC. Lipowski ZJ. 40. Mental disorders: glossary and guide to their classification in accordance with the 10th revision of the international classification of diseases. McDaniel JS.7:267-270. Lipowski ZJ. 42. Robins E. World Health Organization (WHO). New York State Psychiatric Institute. Arch Gen Psychiatry 1978. Nemeroff CB.7:479-491. Young C.7:94-98.35:47-54. 33. Teague GB. J Palliat Care 1991 . Delirium as a contributing factor to "crescendo" pain: three case reports. Sniath RP. Brown FW. eds. Posner JB. et al.J Palliat Care 1995 (in press). 28. 18. 45. 1979:644-651. The cognitive effects of the administration of narcotic analgesics in patients with c a n c e r pain. Psychometric properties of the Beck Depression Inventory: twentyfive years of evaluation. 1993:1-19. Washingon. Cognitive failure in patients with terminal cancer: a prospective longitudinal study [abst]. Bruera E. 1988. Steer RA. 50. Silberfarb PM.9:44-47. 24. Robins LN. Holland J. Diagnostic and statistical manual of mental disorders. DC: APA. Cohen-Cole SA. 140:1048--1050. 21.7:101-106. 20. JAMA 1987. Bruera E. Washington. Annu Rev Med 1983. 39.6:7-15. Stiefel F. Lichter I.34: 35-46.67: 361-370. Chemotherapy and cognitive defects in cancer patients. Diagnostic criteria for delirium: an empirical study. Ratcliff KF. NewYork: Raven. Principles of medical psychiatry. Silberfarb P. 41. Levkoff S. Gerbin MG. Delirium in terminally ill cancer patients. Philadelphia: WB Saunders. Reversible narcotic associated mental status impairment in patients with metastatic cancer. Structured clinical interview for DSM-III-R. Gen Hosp Psychiatry 1985. 43. 48. Spitzer RL. Depression in the medically ill. 36. 10 No.42:13851391. Fainsinger R. 32. 1987. Bruera E. Stiefel F. MacEachern T. 27. Glass E. New York: Oxford University Press 1995 (in press). Case report: severe organic brain syndrome. 31. Fainsinger RL. Croughan J. 6:492-494. J Pain Symptom Manage 1992. Fainsinger R. Cecil textbook of medicine. Cancer Invest 1989. New York: Brunner/Mazel. Diagnostic assessment of depression in the medically ill. Biometrics Research Department. McDaniel S. Cognitive failure in a terminally ill patient. Acute confusional states in patients with advanced cancer. H u n t E. Endicott J. Arch Gen Psychiatry 1981. Clin Psychol Rev 1988. 1993. Bruera E. Delirium in cancer patients. Beck AT. Cancer 1984. 22. 1980. Spitzer R.35:773-782. 29. Delirium and exogenous metabolic brain disease. 1991: 12-56. In: Beeson PB. 49. 35. Macmillan K. DC: APA. Littlefield C. Pain 1989. Am J Psychiatry 1991. Am J Psychiatry 1983. Cancer 1978. Acta Psychiatr Scand 1983. Delirium (acute confusional states). 44. HollandJ. Mental disorders in cancer patients. MacDonald RN. DSM-III. Trzepacz PT. eds. eds. 2nd ed. Cognitive failure in patients with terminal cancer: a prospective study. J Pain Symptom Manage 1992. Bruera E. Patersol~ AH. Pharmacology 1987. Goodman H. Coyle N. Depression in the cancer patient diagnostic biological and treatment aspects. Fainsinger R. Brenneis C. Leipzig R. The hospital anxiety and depression scale.9:308. 37. Tucker GJ.J Pain Symptom Manage 1992. Cancer Treat Rep 1987. Geneva: WHO. 23. DSM-IV Organic Disorders Work 25. 38. Symptom control during the last week of life in a palliative care unit. Kuehn N.7:36-38.8:77100. Williams J. 3rd ed. Endicott J.38:381-389. In: Chapman CR. Levine PM. Wyngaarden JB. MacCallion J. The assessment of pain intensity in patients with cognitive failure: a preliminary report. Miller MJ. Lipowski ZJ. Geneva: WHO.

78. Brescia F. Bernhard MR. et al. Roca E. Jaeger H.7:353-360.72:85-92. 73. Use of psychostimulants in medically ill depressed patients. 72. Holland JC. 64. Navlakha PL. A survey of psychotropic use in terminal cancer patients. 66. Costa D. Stiefel FR. Mermelstein HT. Inouye SK. Morrow G. Int Psychogeriatr 1992. A critique of instruments and methods to detect. Goldman A. Reilly C. Psychosomatics 1985. Eastman E. J Consult Clin Psychol 1984. 9:1004-1009. A survey of psychotropic drug prescriptions in an oncology population. Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients. J Psychiatr Res 1975. Levkoff S. et al.52:712-713.1:199-215. Depression in patients with cancer. Romaniuk M. 60. 74. Derogatis LR. Only a small number of clinical depressed cancer patients can be managed by drugs. 55. Int Psychogeriatr 1991. Katzman R. Richardson JS. Psychiatr Res 1988. Chacon R. Crisis interventions: a functional model for hospitalized cancer patients. Kornblith A. Golonka L. Mogos I. et al. 75. Lesko L. et al. et al. The delirium symptom interview: an interview for the detection of delirium symptoms in hospitalized patients. Morrow GR. Cancer 1990. Validity of the short Portable Mental Status Questionnaire with elderly psychiatric patients. Review of research instruments and techniques used to detect delirium.140: 734-739. Acta Psychiatr Scand 1980. Cancer Treat Rep 1986. Eshpumiyani R.3:253-272. Alessi CA. Burnell G. et al. Baker RW.86:40-46. Holland JC. Am J Orthopsychiatr 1979. 70:295-298. May:46. Chitwood J. Treatment of depression in cancer patients is associated with better life adaptation: a pilot study.26:245-248. Delgado A. Robinson C.72:81-84.March 25:5. Double-blind evaluation of the effects of mazindol on pain. anxiety. Nuts Mirror 1979. Farash J. Miller PS. promising in treatment of depression in cancer patients. 56. Psychosomatics 1992. Diss Abst Int 1979. McHugh PR. Schmale A. .37:6362-6363.39:334027. Folstein MF.1:89-97. Acta Psychiatr Scand 1985. A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. 58. "Minimental status": a practical method for grading the cognitive state of patients for clinicians.49:598607. Diss Abst Int 1977. Smith MJ. et al.1:50-98.44:1919-1929. 83. et al. Strain JJ. Ferlie M. Ross R. Fuld P. Group counseling in adult patients with advanced cancer.33:352-356. 67. Vandyck CH. McCartney C. a new method for detection of delirium. 69. Greenhouse J. Evans D. Vol. 71. Jacobs JC. Westie K. depression. Toma T.23:817-819. Screening for organic mental syndromes in the medically ill.44:760-766. Delirium acute confusional states: evaluation devices in nursing. appetite and activity in terminal cancer patients. Carroll B. Levkoff SE.113:941-948. Am J Psychiatr 1988. 61. Modi RS. Tarrier N. Cancer 1979. Platt MM. Albert MS. Counseling removes patients' fears. 81. 65.47. Lansky S. Maguire P. Goldberg GJ. Liptzin B. 77. 62.65:1048-1053. Feldstein M. Bruera E. The use of group counseling with breast cancer patients receiving chemotherapy. Breitbart W. Haggerty J. Psychiatr Times 1990. Breitbart WS. Psychosomatics 1982. 63. Effect of counseling on resolution of loss of body image disturbances following mastectomy. Hopwood P. 76. l O No. 68. Carraro S.140 Breitbart et al. 26:745-751.8:38-40. Mermelstein H. Changes in prescription patterns of psychotropic drugs for cancer patients during a 10-year period. et al. Jyn IA. Folstein SE.IV: proposals for revision of diagnostic criteria for delirium. Alprazolam. Brown T. Wolber G. diagnose.3:197208. and rate delirium. J Geri atr Psychiatry Neurol 1991 . Clarifying confusion: the confusion assessment method. Mor V. 70. Ann Intern Med 1990. 82. 52. Pemoline: an alternative psychostimulant for the management of depressive disorders in cancer patients. Bloom J. Clin Psychiatr News 1978. Kennedy BJ. Capone M. A symptom rating scale for delirium. Jones E. 59. Baum M. 79. Am J Psychiatry 1983. Efficacy and safety of mianserin in the treatment of depression of women with cancer.J Assoc Phys India 1978. The role of antidepressants in hospitalized cancer patients. Patient Counsel Health Educ 1978.3:301-308. Williams MA. 53. Kaufman MW. Psychosom Med 1987. Murray GB. Barugel M. 2February 1995 Group. Int Psychogeriatr 1991. Purohit DR. Ann Intern Med 1977. Morrow G.J Clin Onco11991. Psychooncology 1992. Cassem NH. Cleary P. Cancer 1979.50:72-76.145:342-345. Validation of a short orientation-memory-concentration test of cognitive impairment. Trzepacz PT. 54. A survey of psychotropic drug utilization by patients with advanced neoplastic disease. J Pain Symptom Manage 1995. 80.5:14-21. Treatment of depression in cancer patients.10:3577. DSM.12:189-198. 57. The effect of social support on patients adjustment after breast cancer. Gen Hosp Psychiatry 1985.

Lancet 1988. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 141 84.5:183-189. Ross CA. Diller L. 104.48:743-759. Shapiro I. Folstein MF. Psychosocial benefits of a cancer support group.19:165-172. Linn BS. 105.324: 746-752. et al.49:239-241. 95.108:277-288.40:17-20. Cancer 1986. Wool M. Stiefel F. et al. May 11-16. Arch Gen Psychiatry 1990. 92. 1991.1:67-68. Management of delirium in terminally ill AIDS patients. Recent Results Cancer Res 1988.48:163-166. J Neuropsychiatr Clin Neurosci 1994. Thompson WL. Preventive psychosocial interventions with newly diagnosed cancer patients. et al. 144th Annual Meeting in New Orleans.Vol. Greidenbergs I. J Am Geriatr Soc 1971. 37th Annual Meeting in Phoenix.6:243-249. Adjuvant psychological therapy for patients with cancer: a prospective randomized trial.Jacobsen P. Forester B. Efficacy of psychosocial intervention with cancer patients. Cole JO. Kuehn N.7: 25-26. KavanaughJJ. Psychosomatics 1974. Zielstra E. Psychotherapy for the spouses of lung cancer patients: assessment of an intervention. Washington. Delirium: phenomenologic and etiologic subtypes. Cancer 1982. Tait A. Group coping skill instruction and supportive group therapy for cancer patients: a comparison of strategies. Double-blind comparison of haloperidol and thioridazine in geriatric outpatients. Telch C.21: 407-413. Fawzy F. 110. Ann Emerg Med 1992. Brooke M. A structured psychiatric intervention for cancer patient: changes over time in methods of coping and mood disturbance.J Consult Clin Psychol 1980. Cain E. Schwartz E. 88. Group support for metastatic cancer patients: a randomized prospective outcome study. Holmes VF. 106. Jepson BA.304:675680.142:22-27. Breitbart W. Bloom JR. Macmillan K.54:802--808. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Clozapine: a novel antipsychotic agent.19:593-600. 93. Tsuang MM. Haloperidol versus thioridazine for hospitalized psychogeriatrics patients: double-blind study. N Engl J Med 1991. Pain 1992. BMJ 1980. 89. 101. Bruera E. Adams F. 99. Strand B. Moorey S. Psychostimulants for hypoactive hypoalert delirium? J Palliat Care 1991. Psychotherapy during radiotherapy: effect on emotional and physical distress. Levy JF. Marotta R. Haloperidol versus thioridazine for the treatment of psychogeriatric patients: a double-blind clinical trial. Marotta R.6:66-67. Peyser CE. Corbera K.15:134-138. Breitbart W. Psychother Psychosom 1985.49:1048-1055. 109. 1990. Lynn MW. Mansell PWA. Spiegel D. Smith GR. Gen Hosp Psychiatry 1984. Effects of modeling on depression and anxiety in adult cancer patients. DC: American Psychiatric Press. Linkons P.38:527533. Miller MJ. Weisman A. 85. 91.43:141-150. 100. Frankenburg F. Efficacy of neuroleptics for hypoactive delirium [Letter]. The effects of counseling on psychiatric morbidity associated with mastectomy. Bruera E. Sellwood R. Thomas H. Low-dose neuroleptic treatment for AIDS delirium. Stotsky BA. 97. In: American Psychiatric Association. Gordon WA. Pharmacologic management of delirium in medically hospitalized AIDS patients. Bloom J. 112. Petrilli R. et al. Fernandez F. LA.45:333-339. Ann Intern Med 1975. 90. Smith M. Worden J. 103. Breitbart W. BMJ 1992. November 15-18. Lu LM. 96. Diss Abst Int 1990. In: Academy Psychosomatic Medicine. Telch M.40:3973. Int J Psychiatr Med 1989. AmJ Psychiatr 1985. Kohorn DM. Bos-Branoite G. Yalom I. Platt M. Group therapy and hypnosis reduce metastatic breast carcinoma pain. et al. Psychosomat Med 1983. Kornfield D. Platt M. Greer S. Spiegel D. Efficacy of counseling for late stage cancer patients. Maguire P. J Consult Clin Psychol 1986. Taylor CW. J Clin Psychiatry 1979. Goldberg R. Psychotherapy in patients cured of gynecological cancer. . Fawzy N. 108. 107.47:720-725.82:175-180. Rosen JH. Baldessarini R. Midazolam in terminal care. Fliess J. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. J Clin Psychiatry 1988. Thomas C. 86. 102. Int Psychogeriatr 1991. Cousin N. 94. et al. Johnson AD. Baruch JD. 98. 28:1454-1456. Osier Medical Housestaff: diazepam and paraldehyde for treatment of severe delirium tremens. Marotta R. Platt M. Fernandez F. 87. Maddrey WL. 111.3:135-147. AZ. Treatment of severe refractory agitation with a haldol drip. DeSousa AE. Haris R. Weisman H. Arch Gen Psychiatr 1981. 10 No. Quinlan K. Rianshouwer Y.

Sign up to vote on this title
UsefulNot useful