Breitbart 1995 Journal of Pain and Symptom Management

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 General Hospital (M.L.), Halifax, Nova Scotia, Canada

Abstract This article represents the contributions of the panel on "Neuropsychiatric Syndromes 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 to fiU 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) encouragement for studies of the prevalence of neuropsychiatric symptoms and syndromes, (5) promotion of intervention studies utilizing pharvnacologic and nonpharmacologic treatments for 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, depression, cognitive disorders

neuropsychiatric syndromes, psychological symptoms,

Introduction

The National Cancer Institute of Canada Workshop on Symptom Control and Suppor- tive Care in Patients with Advanced Cancer, which took place on October 28-29, 1993, included an afternoon session on "Neuropsy-

Address reprint requests to: William Breitbart, MD, Memorial Sloan-Kettering Cancer Center, Box 421, 1275 York Avenue, New York, NY 10021, USA. Accepted for publication: June 20, 1994.

chiatric Syndromes and Psychological Symp- toms 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

© U.S. Cancer Pain Relief Committee, 1995 0885-3924/95/$9.50 Published by Elsevier, NewYork, NewYork SSDI 0885-3924(94)00075-V

132 Breitbart et al. Vol. 10 No. 2 February 1995

regarding prevalence, assessment, and treatment of neuropsychiatric syndromes and symptoms (focusing on depression and delirium) in the advanced cancer patient. Highlighted in the presentations and the discussions following were inadequately developed areas of research, methodologic problems impeding progress of research, and strategies for overcoming obsta- cles to research on neuropsychiatric syndromes and symptoms in the palliative care setting. Specific recommendat ions for future research focus in this area were made and are described here.

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; (b) symptoms and syndromes of a neuropsychiatric nature, such as mood disorders (depression), cognitive impairment disorders, anxiety, in- somnia, and suicidal ideation, have an important place in any agenda that focuses on symptom control in the advanced cancer patient; (c) neuropsychiatric symptoms and syndromes must be unders tood in the following contexts: (1) they coexist with multiple other physical and psychological symptoms and interact with them, (2) they cannot be studied in isolation, and (3) they must be understood in the context of the patient and family as the unit of concern; and (d) neuropsychiatric disturbance studies should be approached on two levels, that is, both as symptoms and as syndromes or disorders whenever possible.

The evidence presented by the panel speaks to the high prevalence of neuropsychiatric syndromes and symptoms in the advanced cancer patient, the significant associated morbidity, and the paucity of clinical research to date in the areas of assessment and treatment or intervention. The following is a brief re~4ew of the panel's presentations on mood disorders, cognitive disorders, and pharmacotherapies.

Mood Disorders Presentations and discussions in this section

focused primarily on the syndrome of major depression. Prevalence rates for major depressive syndromes in cancer patients range from

4.5% to 58% based on psychiatric consultation database studies 1-4 and research based prevalence studies. 5-15 Only a limited n u m b er of these studies examined prevalence of depression in cancer patients with far-advanced disease, 1,'~,7,1~t5 and these suggest that depression is more co m m o n in later stages of cancer, ranging in prevalence from 23% to 58%. Reports also suggest that depression is associated with increased morbidity, in cancer pa- fients.:~-16

The broad variation in the repor ted prevalence of depression is due to the problems of terminology, methodology, and the applica- tion of diagnostic systems not originally in- tended for use in medically ill populations. These problems present a general obstacle to the study of depression in advanced cancer patients. To diminish these problems, one must first distinguish between symptoms and syndromes. The symptom of sadness or depressed mood is not equivalent to the syndrome of major depression. Several of the studies on the prevalence of depression exam- ine levels of severity of depressive symptoms (often as repor ted by patients on self-report measures such as the Beck Depression Inven- tory) and do not reflect rates of diagnosis of the specific clinical syndrome of major depression (although they may be highly correlated). Distinguishing between normal sadness and the syndrome of major depression in advanced cancer patients has important t reatment impli- cations.

Table 1 lists the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised 17 (DSM-III-R), criteria for a diagnosis of major depressive syndrome. The DSM-III-R (soon to be DSM-1V) classification system for psychiatric disorders is the most widely used diagnostic system in North America. Utilization of the different diagnostic classification systems, DSM-III, DSM- III-R, and Research Diag- nostic Criteria (RDC), is often leads to widely varying rates of detection of depression in cancer patients. Kathol and colleagues 1:~ found as much as a 13% difference in rates of major depression when utilizing criteria of the DSM- III (38%), DSM-III-R (29%), and RDC (25%). 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.

VoL 10 No. 2 February 1995 Neuropsychiatric ,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. Depressed mood, dysphoria, loss of interest or pleasure, or anhedonia (at least one symptom must be from this group)

2 Physical/somatic symptoms: sleep disorder, appetite or weight change, or fatigue or loss of energy

3. Psychological/cognitive symptoms:worthless- ness/guilt, indecisiveness/poor concentration, or thoughts of death/suicidal ideation

Adapted from reference 17.

Four di f ferent approaches to the diagnosis o f major depress ion in the cancer pat ient have been describedlg,2°: (a) an inclusive ap- p r o a c h - i n c l u d e s all symptoms whe the r or no t they may be secondary to cancer illness or t rea tment ; (b) an exclusive a p p r o a c h - - d e l e t e s and disregards all physical symptoms f r o m considera t ion, no t allowing them to con t r ibu te to a diagnosis o f major depressive syndrome; (c) an etiologic a p p r o a c h - - t h e clinician at- tempts to de te rmine if the physical symptom is due to cancer illness o r t r ea tment (and so does no t include it) or due to a depressive d i sorder (in which case it is inc luded as a cr i ter ion symptom) ; and (d) a substitutive a p p r o a c h - - where physical symptoms of uncer ta in et iology are rep laced by o the r nonsomat ic symptoms. The latter app roach is best exemplif ied by the Endico t t Substi tution Criteria, 21 listed in Table 2 and utilized in studies by Kathol and colleagues l~ and C h o c h i n o v and colleagues. 14 C h o c h i n o v and colleagues J4 s tudied the prevalence o f depress ion in a terminally ill c ance r

Table 2 Endicott Substitution Criteria

Physical/somatic Psychological symptom symptom substitute

1. Change in appetite, weight

2. Sleep disturbance

3. Fatigue, loss of energy

4. Diminished ability to think or concentrate, indecisiveness

1. Tearfulness, depressed appearance

2. Social withdrawal, decreased talkativeness

3. Brooding, self-pit),, pessimism

4. Lack of reactivity

popu la t ion and c o m p a r e d low versus high diagnostic thresholds, as well as Endico t t substi- tut ion criteria. Interestingly, identical prevalence rates o f 9.2% for major depress ion and 3.8% for m i n o r depress ion (total = 13%) were f o u n d util izing RDC high th resho ld criteria and h igh- threshold Endicot t criteria.

Research assessment me thods for depressive disorders in cancer patients have b e c o m e m o r e sophisticated, valid and reliable. Table 3 lists a n u m b e r o f available assessment me thods for depression, inc luding diagnostic classification systems, s t ruc tured diagnostic interviews, and sc reen ing instruments . Unfor tunate ly , few studies o f depress ion in terminally ill or advanced cancer patients have used such research assessment me thods to date. Addit ion- ally, fu r the r work is necessary in adap t ing to the l imitations o f such me thods in their applica- tion to popula t ions with advanced cancer .

Cognitive Disorders Presenta t ions and discussions in this section

focused primari ly on the synd rome of delir ium. Del i r ium has been def ined as "a t ransient organic brain syndrome charac ter ized by the acute onset of d i sordered a t ten t ion and cognition, a c c o m p a n i e d by d is turbances o f psycho- m o t o r behav ior and percept ion . ''z7 Cognit ive disorders, and del i r ium in part icular, have e n o r m o u s relevance to symptom cont ro l and support ive care. Del i r ium is highly prevalent in cancer pat ients with advanced disease, part icu- larly in the last weeks o f life, with prevalence

Table 3 Research Assessment Methods for

Depression in Cancer Patients

Diagnostic classification systems Diagnostic and Statistical Manual DSM-III, III-R, 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-R 2:~ (SCID)

Screening instruments--self-report General Health Questionnaire-30 ~4 (GHQ) Hospital Anxiety and Depression Scale 25 (HADS) Beck Depression Inventory z6 (BDI)

"Designed for use with RDC criteria. bDesigned for use with DSM-III criteria.


Table 4 DSM-IIIoR Classification Organic Mental Disorders ~

293.00 Delirium 294.10 Dementia 294.00 Amnestic disorder 293.81 Organic delusional disorder 293.82 Organic hallucinosis 293.83 Organic mood disorder 294.80 Organic anxiety disorder 310.10 Organic personality disorder 294.80 Organic mental disorder (NOS) b

Adapted IYom reference 51. "Associated with physical disorders or conditions, or whose etiology is unknown. b NOS, not otherwise specified

rates ranging from 25% to 8 5 % . 28-35 Delirium is associated with increased morbidity in the terminally ill, causing distress in patients, family members, and staff. :¢4,%,:~7 Delirium can interfere dramatically with the recognit ion and control of other physical and psychological symptoms, such as pain, 38-4° in later stages of illness. Often a preterminal event, delirium has multiple etiologies in the advanced cancer patient, including infection, organ failure, chemotherapy and other medication side effects (including opioids), and rare paraneo- plastic syndromes. 41-46

Unfortunately, delirium is underrecognized and undertreated. It is an area underre- searched in palliative medicine. Impediments to progress in t reatment and research in delirium have included confusion regarding terminology and lack of consistency in utilizing diagnostic classification systems. Multiple terms are often used to refer to similar cognitive disorders: delirium, reversible dementia, acute confusional states, cognitive failure, encephalo- pathy, organic brain syndrome, and organic mental disorder. Clinical case studies or research reports that utilize various or idiosyn- cratic terminologies are less helpful contributions to the literature than those that use standard, uniform terminology or diagnostic classification systems. Table 4 lists the types of organic mental disorders described in the DSM-III-R classification system, which is the most widely used system in North America. 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 number of research diagnostic tools and the

current International Classification of Diseases (ICD-9, ICD-10) 48,49 diagnostic classification system. In an empirical study of diagnostic criteria for delirium, 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, DSM-III-R, and ICD-10 research criteria. Prevalence of delirium ranged from 38% to 9% with DSM-III criteria being most inclusive (38%), DSM-III-R being some- what less inclusive (33%), and the ICD-10 research criteria being least inclusive (9%).

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. Both the DSM and ICD systems are being revised again, with ICD-10 and DSM-IV systems due to appear shortly. In DSM- IV, 51 the "organic mental disorders" are being eliminated and replaced by "cognitive impairment disorders,"which are listed and described in Table 5. The "organic" mood, anxiety, personality, and delusional disorders will be relocated and included in the major diagnostic groups, and listed as secondary disorders. It is anticipated that the DSM-IV classification system for cognitive impairment disorders will replace DSM-III-R as the domi- nant diagnostic system in North America.

Table 5 Proposed DSM-IV Cognitive Impairment Disorders

A. General cognitive impairment 1. Delirium

a. Delirium due to a general medical condition b. Substance-induced delirium c. Delirium due to multiple etiologies d. Delirium not otherwise specified

2. Dementia a. Dementia of the Alzheimer's type b, Vascular dementia c. Dementia due to other medical conditions d. Substance-induced persisting dementia e. Dementia due to multiple etiologies f. Dementia not otherwise specified

B. Specific cognitive impairment 1. Amnestic disorders

a. Amnestic disorder due to a general medical condition

b. Substance-induced persisting amnestic disorder c. Amnestic disorder not otherwise specified

C. Cognitive disorder not otherwise specified

Adapted fi'om reference 51.

Vol. 10 No. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 135

Table 6 Proposed DSM-IV Criteria for Delirium

293.00 Delirium due to a general medical condition

A. Disturbance of consciousness (that is, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.

B. Change in cognition (such as memory deficit, disorientation, language disturbance, or perceptual disturbance) that is not better accounted for by a preexisting, established, or evolving dementia.

C. The disturbance develops over a sort period of time (usually hours to days) and tends to fluctuate during the course of the day.

D. There is evidence from the history, physical examination, or laboratory findings of a general medical condition judged to be etiologically related to the disturbance.

Adapted from retbrence 51.

Despite changes in the classification o f organic menta l disorders or cognitive impair- m e n t disorders made in the evolution f rom DSM-III to DSM-III-R to DSM-1V, the essential nature o f del i r ium as a synd rome has been maintained. Table 6 lists the DSM-IV criteria for del i r ium T h e essential features o f acute onset o f d i so rdered a t tent ion and cogni t ion are retained. Associated p h e n o m e n a such as p sychomoto r behavioral changes , perceptual disturbances, hal lucinat ions, or delusions are no longer viewed as essential to the diagnosis o f delirium.

Research assessment me thods for del i r ium in advanced cancer patients are listed in Table 7, and have been reviewed extensively else- where. 52-62 Only a l imited 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 assess- m e n t methods .

Pharmacotherapies Presentat ions and discussions in this section

focused primari ly on pha rmaco log ic interventions for the t r ea tmen t o f major depressive syndromes and delir ium. Several surveys o f psychotropic d r u g utilization in hospital ized cancer patients, inc lud ing those with advanced disease, reveal tha t ant idepressants and antipsychotics are vastly u n d e r u s e d and that the majority o f pat ients with depress ion and delirium go unt rea ted . 63-66 Ant idepressants are prescr ibed for the t r ea tmen t o f depress ion in

only 1%-3% o f hospi tal ized cancer pat ients 6s,64 and up to 5% o f terminally ill cancer patients, 65,c'6 despite an est imated prevalence o f ma jo r depress ion in advanced cancer patients o f 23%-58%. Ant ipsychot ic neuro lep t ic drugs (dopamine-b lock ing drugs) , are utilized fre- quent ly as antiemetics, but only 0 .5%-2% o f hospi tal ized cancer patients receive haloper i - dol for the m a n a g e m e n t o f the symptoms related to del i r iumfi :~,64 In terminally ill populations, as many as 17% receive an ant ipsychotic for agitat ion o r psychological distress, despite an es t imated prevalence o f del i r ium rang ing f rom 25% in the hospital ized cancer pat ient to 85% in the terminally ill.

The re are few cont ro l led studies o f antidepressant d r u g t r ea tmen t for depressive disorders in cancer pat ients in general and even fewer that focus on the terminally ill. 67-74 To date, imipramine , ~s,72 nortriptyline, 71 mianserin 69,7° and a lprazolam 7:~,74 have been studied and shown effective in cont ro l led trials. MI o f these studies t rea ted cancer patients with depressive symptoms o f a certain th reshold o f severity based on observer-rated o r self-report measures o f depress ion, distress, o r anxiety. N o n e utilized s t ruc tured diagnostic interviews to establish DSM-III, DSM-III-R, or RDC diag- noses o f major depress ion. O f the two controlled trials in the terminally ill populat ions , one study 7] o f nor t r iptyl ine was no t comple t ed because o f high attr i t ion rates due to d rug side effects and disease progression, and a n o t h e r

Table 7 Research Assessment Methods for Delirium in

Cancer Patients

Diagnostic classification systems DSM-III, DSM-III-R, DSM-IV ICD-9, ICD-10

Diagnostic inter~fiews/instruments Delirium Symptom Interview 54 (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 Test 62

(BOMC)


study of alprazolam 7:~ contained a sample of only 20 patients. Psychostimulants (for example, methylphenidate , dex t roamphetamine , pemoline , and mazindol) have been shown to be effective antidepressants in cancer patients and other medically ill populations. 75 Bruera and colleagues 76 studied mazindol 's effects on depression in terminally ill cancer patients utilizing a double-blind design. Pemoline was also shown to be an effective ant idepressant particularly useful for terminally ill patients, with no available oral route for drug administration, who could utilize the chewable tablets for buccal absorption. 77 Table 8 lists the currently available drugs useful in the treat- men t of depression in cancer patients with advanced illness. Newer agents with fewer side effects and simplified dosage regimens, such as the serotonin-specific reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine), and the reversible inhibitors of m o n o a m i n e oxidase subtype A (RIMA), such as clorgyline (not yet available) and moclobemide, may have impor tant applications in treating depression in patients with advanced cancer. Control led trials of these newer agents for the t rea tment of depression in patients with advanced disease are necessary. A n u m b e r of psychotherapy-intervention trials for the treat- men t of psychological distress and depression have been conducted with cancer patients, but few, if any, have included patients with far- advanced disease. 7s-:)7

A standard approach 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, correction of those factors, and m a n a g e m e n t of the symptoms of delirium. ~7,:~i The treat- men t of delirium in the dying cancer pat ient is in fact unique and presents certain dilemmas. Most often the etiology of terminal delirium is multifactorial or may not be determined. Bruera and colleagues ss repor t that an etiology was discovered in less than 50% of terminally ill patients with cognitive failure. When a distinct cause is found for delirium in the terminally ill, it is often irreversible or difficult to treat. Diagnostic workup in pursuit of an etiology for delirium may be limited by the setting (home, hospice) or the focus on pat ient comfort , so that unpleasant or painful diagnostics may be avoided. A debate is now ongoing as to the appropr ia te extent of diagnostic evaluation

Table 8 Antidepressant Medications Used in Advanced

Cancer Patients

Therapeutic daily Drug dosage mg (oral)

Tricyclic antidepressants Amitriptyline 25-125 Doxepin 25-125 Imipramine 25-125 Desipramine 25-125 Nortriptyline 25-125 Clomipramine 25-125

Second-generation antidepressants Burpropion 200-450 Trazodone 150-300

Heterocyclic antidepressants Maprotiline 50-75 .4anoxapine 100-150

Serotonin-specific reuptake inhibitors Fluoxetine 20 Sertraline 50-200 Paroxetine 10-50 Fluvoxamine 50-300

Monoamine oxidase inhibitors Isocarboxazid 20-40 Phenelzine 30-60 Tranylcypromine 20-40 Moclobemide 100-600

Psychostimulants Dextroamphetamine 5-30 Methylphenidate 5-30 Pemoline 37.5-150

Benzodiazepines Alprazolam 0.75-6.00

Adapted frOlil reti_~rence 4.

versus the risk or benefi t as they pertain to delirium. :~j,:~:~,:sS,:~s More research in this area is needed to help guide clinicians. In addit ion to seeking out and potentially correct ing underlying causes for delirium, symptomatic and supportive therapies are important . 27,:~1,:~,:~5,:~s In fact, in the dying patient, they may be the only steps taken. Fluid and electrolyte balance, nutrition, vitamins, measures to help reduce anxiety and disorientation, and interactions with and education of family member s may be useful. Such supportive measures have not been studied in terms of their impact on the symptoms of delirium.

Often however, these supportive techniques alone are not effective, and symptomatic treat- men t with neurolept ic or sedative medicat ions are necessary (Table 9). Haloperidol , a neuroleptic drug that is a potent dopamine blocker, is the agent of choice in the t r ea tment

VoL I0 No. 2 February 1995 Neuropsychiatric Syndromes and Advanced Cancer 137

Table 9 Medications for Managing Delirium in Advanced

Cancer Patients

Approximate daily dosage Generic name range route.

Neuro lep t i c s Ha lope r ido l

T h i o r o d a z i n e C h l o r p r o m a z i n e

M e t h o t r i m e p r a z i n e

Benzod iazep ines L o r a z e p a m

Midazo lam

0 .5 -5 m g every 2-12 h r PO, IV,, SC, IM

10-75 mg every 4-8 hr PO 12.5-50 mg every 4-12 hr PO,

IV, IM 12.5-50 mg every 4-8 hr IV,

SC, PO

0.5-2 .0 m g every 1-4 h r PO, Iv, IM

30-100 m g every 24 h r IV,, SC

Parenteral doses are generally twice as potent as oral do~s . IV, intravenous bolus injections or infusions should be administered slowly; IM, intramuscular injections should be avoided if repeated use becomes necessaw; PO, oral forms of medication are preferred; or SC, subcutaneous infusions a r e

generally accepted modes of drug administration in the terminally ill.

phenomenologies and etiologies.I°8 Therefore hypoactive and hyperactive deliria may require different t reatment strategies. While some investigators suggest that neuroleptics may be equally effective for both subtypes of delirium, 1°9 others suggest that hypoactive delirium may best respond to psychostimulants or combinations of neuroleptics and stimulant. 11° Stimulants may also play a role in the management of terminally ill patients with various cognitive impairment disorders exper ienced by patients on opioid infusions, ill Newer antipsychotic agents are being developed that have more specific or no dopamine antagonist effects and fewer neurologic side effects (that is, extra pyramidal effects or tardive dyskinesia) such as clozaril or sulpiride, if2 These new agents and newer antipsychotics that will become available in the near future may have impor tant roles in managing delirium in the terminally ill.

of delirium in the medically ill. 27,9s It is often combined with a benzodiazepine drug such as lorazepam. 99 The palliative care /hospice literature also describes the use of methotrime- prazine, a phenothiazine neuroleptic, and midazolam, a short acting benzodiazepine usually administered as continuous infusions for the management of agitation and terminal delirium. 31,s:~,~5'ss,l°°-l°4 There are few controlled trials of neuroleptic agents in the management of delirium or agitation due to organic mental disorders 1°1-1°4 and even fewer that have been conducted in terminally ill patients.l°5-J°7 More controlled, comparison trials of various agents or combinations of agents in the management of delirium in the terminally ill are necessary.

Several interesting clinical questions in this area exist, and more research could helpfully inform clinical management. 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, family, and staff?. What are effective pharmacologic and nonpharmacologic interventions? An interesting, currently important topic is that of differential therapeutics. Hy- poactive and hyperactive subtypes of delirium have been described, and seem to have distinct

Specific Recommendations for Future Research

Recommendat ions for future research in the area of neuropsychiatric syndromes and psychological symptoms are based on a consensus of the panel and workshop participants. Rec- ommendat ions are made with the in tended goals of improving the quality of research in this area of palliative medicine and a desire to fill glaring gaps in our current state of knowledge. Specific recommendat ions include:

1. Studies of neuropsychiatric symptoms/ syndromes should adopt the use of uniform terminology (taxonomy of disorders) and diagnostic classification systems wherever relevant and available.

2. Existing validated tools and measures should be utilized in prevalence and intervention research in neuropsychiatric symptoms and syndromes (Tables 3 and 7).

3. 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, need to be developed.

4. Prevalence studies of neuropsychiatric syndromes and symptoms should be encouraged. Of particular interest are studies in special palliative care populations (that is,


elderly, children, terminally ill, those receiving opioids, and those with preexist ing dementia) , and settings (hospital, h o m e care, hospice, and palliative care units).

5. Intervention studies utilizing pharmacologic and nonpharmacolog ic t reatments for neuropsychiatric syndromes and symptoms should be encouraged. In depressive disorders, more controlled trials of ant idepressant efficacy in the t rea tment of depression in advanced cancer patients are needed. Studies examining the efficacy for depression of psychostimulants, serotonin-specific reuptake inhibitors, and other new agents that may be more tolerable in advanced cancer patients are also needed. Studies examining the pharma- cokinetics and pharmacodynamics of antidepressant drugs in advanced cancer patients are necessary. Nonpharmacologic interventions alone or in combinat ion with ant idepressant drug treatments should be encouraged. These might include medical interventions such as hydration or psychosocial interventions aimed at patients, families, or staff. The panel also wanted to encourage studies of depression t reatment that utilized novel combinat ions of pharmacologic agents (that is, an SSRI and a psychostimulant) or novel uses of existing agents (that is, hormona l t reatments such as testosterone). In cognitive impa i rment disorders, controlled intervention trials in the t reatment of delirium are needed that focus on (a) comparison of existing agents (haloperidol versus lozepam), (b) combinat ions of agents (haloperidol and st imulant versus haloperidol alone), (c) newer antipsychotic agents as they become available, and (d) nonpharmacolog ic interventions (that is, medical m a n a g e m e n t alone versus drug intervention).

6. Expansion of the focus of research to other neuropsychiatric syndromes symptoms and related issues. The panel felt that prevalence and intervention studies were necessary in several areas affecting advanced cancer patients including (a) anxiety disorder, (b) post traumatic stress disorders, (c) sleep disorders, (d) symptoms such as fatigue and tension, and (e) suicidal ideation and desire for hastened death. The panel also felt that studies that focused on prevent ion of neuropsychiatric syndromes / symptoms as well as studies of cost and impact on families and the health-care system should be encouraged.

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Breitbart 1995 Journal of Pain and Symptom Management

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