- Email: [email protected]
PHARMACOLOGICAL INTERACTIONS
Abstracts favorable side-effect profile associated with few or no drug interactions. This aids in compliance.
elderly or those ⱖ75, although this group may be the most difficult to treat.
DEPRESSION AND DEMENTIA. Ira R. Katz, M.D., Ph.D.
ANTICHOLINERGIC EFFECTS Larry E. Tune, M.D.
L
B
ate-life depression, in general, occurs in the context of comorbid medical/neurological illnesses or other psychiatric disorders, such as dementia. There is evidence that depression remains a diagnosable and treatable disorder in the presence of comorbid conditions as diverse as AD, stroke, Parkinson’s disease, arthritis, cancer, cardiac disease, chronic obstructive pulmonary disease, and diabetes. With increasing knowledge, the questions facing clinicians have advanced from whether depression should be diagnosed and treated to how it should be done. Recent research findings in this area include differential effects of selective serotonin reuptake inhibitors vs. tricyclic antidepressants on glucose control in diabetes, and changes in plasma level-response relationships for nortriptyline in AD. There are ongoing questions about optimal methods for screening for and identifying depression in the face of significant medical illness, and the impact of subcortical/deep white matter hyperintensities on treatment responses.
REVIEW OF AVAILABLE TREATMENTS FOR LATELIFE DEPRESSION. Craig Nelson, M.D.
D
epression is common in late life, especially in patients with medical illness or in institutional health care settings. Fortunately, a variety of treatments are available for patients who develop late-life depression. Both psychotherapy and pharmacotherapy appear to be effective, although the latter has been better studied. In 1988, Gershon et al. found 25 double-blind studies examining depression in late life. Almost all of these were studies of the tricyclic antidepressants (TCAs). Although only 13 of these studies were placebo controlled, in general, they found antidepressants to be effective. In a subsequent review of recent studies by Nelson in 1997, 19 studies of selective serotonin reuptake inhibitor compounds were identified. Thirteen of these studies provided a comparison with a TCA. These studies demonstrated comparable efficacy for the two groups of drugs, but with higher dropout rates associated with the TCAs due to adverse effects. Several studies also demonstrated less adverse effects on cognitive function for the selective serotonin reuptake inhibitors than for the TCAs. The studies provide information about special issues in older adults, such as appropriate dosing and duration of treatment, sensitivity to side effects, resistance to treatment, and drug interactions. Much of the data on elderly patients comes from samples of reasonably healthy patients ⬍ 75. Few studies have been completed in the frail
Am J Geriatr Psychiatry Supplement, Fall 1999
AND
HAZARDS.
ecause of age- and disease-related (e.g., dementia) changes in cholinergic neurotransmission, one important source of “cognitive toxicity” in older adults is the antimuscarinic effect of psychotropic medications either alone (direct anticholinergic toxicity) or in combination with other medications (cumulative anticholinergic toxicity). Data from preclinical and clinical investigations strongly suggest that many antidepressants have significant adverse effects on tests of recent memory, attention, and motor performance. The most toxic of these agents include amitriptyline, imipramine, doxepin, and clomipramine. Preclinical and clinical data include in vitro measurements of the relative antimuscarinic effects of these medications using radioreceptor assay methods. The use of antidepressants in older adults raises greater concerns because of the number of concomitant nonpsychiatric medications with modest antimuscarinic effects. These include commonly prescribed medications like digoxin, furosemide, prednisolone, and cimetidine. Data from published and ongoing studies show significant effects of these medication combinations on measures of behavior, cognition, and activities of daily living. Many antidepressants have little or no cognitive toxicity. In some cases, subtle cognitive enhancing effects have been shown, e.g., sertraline, fluoxetine, and citalopram. These agents should be considered first-line therapy. Antidepressants associated with cognitive toxicity should be avoided.
PHARMACOLOGICAL INTERACTIONS. David J. Greenblatt, M.D.
T
he availability of selective serotonin reuptake inhibitors and related mixed-mechanism antidepressants during the last 10 to 15 years has increased the therapeutic options available for patients with depression but has also reopened the general clinical problem of drug interactions in psychopharmacology. This is of particular concern for older adults, who may be receiving multiple pharmacologic treatments for psychiatric disorders coexisting with other medical disease. Understanding the function and regulation of the human cytochrome P450 (CYP) family of drug-metabolizing enzymes is of considerable value in bringing a vast amount of data on drug interactions into a manageable perspective. The major human CYP enzymes (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) have distinct mechanisms of geriatric control, substrate specificities, and susceptibility to induction and inhibition. Many drug inter-
23
AAGP 12th Annual Meeting actions with selective serotonin reuptake inhibitors and related antidepressants can be understood by their capacity to induce or inhibit the CYP enzymes. As an example, fluoxetine, its metabolite norfluoxetine, and paroxetine are strong CYP2D6 inhibitors and, predictably, cause large and clinically important interactions with drug substrates of CYP2D6. The clinical properties of the CYP enzymes and clinically important drug interactions with antidepressants have strong implications for antidepressant treatment of older adults.
impact of treatment with antidementia drugs on the use of other psychotropic medications used for psychiatric and behavioral problems will also be reviewed. Dr. Steinberg clarifies the existing body of older and newer treatment modalities and will translate this information into current practice approaches and alternatives. With this information, we can optimize treatment by utilizing current medication options that are most appropriate for a particular Alzheimer’s patient.
TRANSLATING DATA INTO OPTIMAL PATIENT CARE: THE ROLE OF THE GERIATRIC PSYCHIATRIST. Jeanne Jackson, M.D.; William E. Reichman, M.D.; Lon S. Schneider, M.D.; Alan Steinberg, M.D.
PHARMACOLOGIC AND PSYCHOPHARMACOLOGIC INTERVENTIONS IN DEMENTIA: WHERE HAVE WE BEEN? Jeanne Jackson, M.D.
T
he objective of this symposium is to expand the role of the geriatric psychiatrist in patient care and to the community. New data regarding psychopharmacologic interventions must be interpreted and applied to patient care. By understanding the newest available data, geriatric psychiatrists will be well-positioned to expand their role as consultants to primary care and long-term care and as educators to the community. Dr. Jackson reviews how traditional approaches in the treatment of Alzheimer’s disease have focused on improving cognitive status by increasing the levels of acetylcholine in the synapse. However, as newer cholinesterase inhibitors have moved through clinical trials, it has become apparent that this simplistic understanding does not explain the unanticipated behavioral benefits seen from these “cognitive enhancers” and that more data is needed. Dr. Reichman highlights other treatment modalities including Ginkgo biloba, vitamin E, selegiline, estrogen, and nonsteroidal anti-inflammatories. The data for newer nicotinic-mediated medications, including galantamine, are also reviewed where Dr. Reichman explores the possibility that nicotinic modulating activity may add to the standard clinical therapeutic benefits. Dr. Schneider presents new analyses of antidementia drug utilization by physicians. By examining more than 5 years of data (IMS America, Inc.), he will describe secular trends in prescribing patterns with the available cholinesterase inhibitors, tacrine, donepezil, and rivastigmine. These analyses describe types of physicians prescribing, indications for prescribing, dosages, number of new prescriptions, and refills. The extent of polypharmacy and comorbid conditions are evaluated, as well as recent effects of the increase in vitamin E usage. For example, preliminary analyses indicate that the median length of a prescription for donepezil is 16 weeks, with a very low proportion of refills. The reasons for this apparently short duration will be further analyzed in the light of existing efficacy data. The
24
T
raditional approaches in treating Alzheimer’s patients focused on behavior management until the advent of acetylcholine enhancers. With the advent of tacrine, treatment of cognitive impairment became possible. Unfortunately, there were numerous problems with side effects, a need for liver monitoring, and the frequent dosing schedule. This presentation briefly reviews the effectiveness of tacrine and the tolerability profile. Donepezil has become the preferred treatment intervention for Alzheimer’s patients, primarily due to the improved side-effect profile and once-a-day dosing. Data are reviewed on donepzil’s ability to delay progression rather than to significantly improve most patients’ cognitive capacity.
NEW HORIZONS IN PHARMACOLOGIC INTERVENTIONS: WHERE ARE WE GOING? William E. Reichman, M.D.
I
n recent years we have seen the introduction of newergeneration cholinesterase inhibitors for the treatment of the cognitive deficits of AD. Donepezil, rivastigmine, metrifonate, and galantamine offer practical as well as theoretical advantages over earlier therapies. While such drugs offer the promise of modest degrees of cognition enhancement and possibly neuroprotection, their potentially beneficial psychotropic properties are also being increasingly recognized. Importantly, the standard pharmacotherapy of AD may also include emerging therapies for neuroprotection such as vitamin E, selegeline, ginko biloba, novel antiinflammatory compounds such as the COXII inhibitors, and estrogens. Anti-amyloid strategies as well as neural transplantation and gene therapy loom on the horizon. This talk focuses on the evolving spectrum of these approaches with a review of the most up-to-date research data available. The promise of these new techniques for the clinical treatment of AD are highlighted.
Am J Geriatr Psychiatry Supplement, Fall 1999
elderly or those ⱖ75, although this group may be the most difficult to treat.
DEPRESSION AND DEMENTIA. Ira R. Katz, M.D., Ph.D.
ANTICHOLINERGIC EFFECTS Larry E. Tune, M.D.
L
B
ate-life depression, in general, occurs in the context of comorbid medical/neurological illnesses or other psychiatric disorders, such as dementia. There is evidence that depression remains a diagnosable and treatable disorder in the presence of comorbid conditions as diverse as AD, stroke, Parkinson’s disease, arthritis, cancer, cardiac disease, chronic obstructive pulmonary disease, and diabetes. With increasing knowledge, the questions facing clinicians have advanced from whether depression should be diagnosed and treated to how it should be done. Recent research findings in this area include differential effects of selective serotonin reuptake inhibitors vs. tricyclic antidepressants on glucose control in diabetes, and changes in plasma level-response relationships for nortriptyline in AD. There are ongoing questions about optimal methods for screening for and identifying depression in the face of significant medical illness, and the impact of subcortical/deep white matter hyperintensities on treatment responses.
REVIEW OF AVAILABLE TREATMENTS FOR LATELIFE DEPRESSION. Craig Nelson, M.D.
D
epression is common in late life, especially in patients with medical illness or in institutional health care settings. Fortunately, a variety of treatments are available for patients who develop late-life depression. Both psychotherapy and pharmacotherapy appear to be effective, although the latter has been better studied. In 1988, Gershon et al. found 25 double-blind studies examining depression in late life. Almost all of these were studies of the tricyclic antidepressants (TCAs). Although only 13 of these studies were placebo controlled, in general, they found antidepressants to be effective. In a subsequent review of recent studies by Nelson in 1997, 19 studies of selective serotonin reuptake inhibitor compounds were identified. Thirteen of these studies provided a comparison with a TCA. These studies demonstrated comparable efficacy for the two groups of drugs, but with higher dropout rates associated with the TCAs due to adverse effects. Several studies also demonstrated less adverse effects on cognitive function for the selective serotonin reuptake inhibitors than for the TCAs. The studies provide information about special issues in older adults, such as appropriate dosing and duration of treatment, sensitivity to side effects, resistance to treatment, and drug interactions. Much of the data on elderly patients comes from samples of reasonably healthy patients ⬍ 75. Few studies have been completed in the frail
Am J Geriatr Psychiatry Supplement, Fall 1999
AND
HAZARDS.
ecause of age- and disease-related (e.g., dementia) changes in cholinergic neurotransmission, one important source of “cognitive toxicity” in older adults is the antimuscarinic effect of psychotropic medications either alone (direct anticholinergic toxicity) or in combination with other medications (cumulative anticholinergic toxicity). Data from preclinical and clinical investigations strongly suggest that many antidepressants have significant adverse effects on tests of recent memory, attention, and motor performance. The most toxic of these agents include amitriptyline, imipramine, doxepin, and clomipramine. Preclinical and clinical data include in vitro measurements of the relative antimuscarinic effects of these medications using radioreceptor assay methods. The use of antidepressants in older adults raises greater concerns because of the number of concomitant nonpsychiatric medications with modest antimuscarinic effects. These include commonly prescribed medications like digoxin, furosemide, prednisolone, and cimetidine. Data from published and ongoing studies show significant effects of these medication combinations on measures of behavior, cognition, and activities of daily living. Many antidepressants have little or no cognitive toxicity. In some cases, subtle cognitive enhancing effects have been shown, e.g., sertraline, fluoxetine, and citalopram. These agents should be considered first-line therapy. Antidepressants associated with cognitive toxicity should be avoided.
PHARMACOLOGICAL INTERACTIONS. David J. Greenblatt, M.D.
T
he availability of selective serotonin reuptake inhibitors and related mixed-mechanism antidepressants during the last 10 to 15 years has increased the therapeutic options available for patients with depression but has also reopened the general clinical problem of drug interactions in psychopharmacology. This is of particular concern for older adults, who may be receiving multiple pharmacologic treatments for psychiatric disorders coexisting with other medical disease. Understanding the function and regulation of the human cytochrome P450 (CYP) family of drug-metabolizing enzymes is of considerable value in bringing a vast amount of data on drug interactions into a manageable perspective. The major human CYP enzymes (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) have distinct mechanisms of geriatric control, substrate specificities, and susceptibility to induction and inhibition. Many drug inter-
23
AAGP 12th Annual Meeting actions with selective serotonin reuptake inhibitors and related antidepressants can be understood by their capacity to induce or inhibit the CYP enzymes. As an example, fluoxetine, its metabolite norfluoxetine, and paroxetine are strong CYP2D6 inhibitors and, predictably, cause large and clinically important interactions with drug substrates of CYP2D6. The clinical properties of the CYP enzymes and clinically important drug interactions with antidepressants have strong implications for antidepressant treatment of older adults.
impact of treatment with antidementia drugs on the use of other psychotropic medications used for psychiatric and behavioral problems will also be reviewed. Dr. Steinberg clarifies the existing body of older and newer treatment modalities and will translate this information into current practice approaches and alternatives. With this information, we can optimize treatment by utilizing current medication options that are most appropriate for a particular Alzheimer’s patient.
TRANSLATING DATA INTO OPTIMAL PATIENT CARE: THE ROLE OF THE GERIATRIC PSYCHIATRIST. Jeanne Jackson, M.D.; William E. Reichman, M.D.; Lon S. Schneider, M.D.; Alan Steinberg, M.D.
PHARMACOLOGIC AND PSYCHOPHARMACOLOGIC INTERVENTIONS IN DEMENTIA: WHERE HAVE WE BEEN? Jeanne Jackson, M.D.
T
he objective of this symposium is to expand the role of the geriatric psychiatrist in patient care and to the community. New data regarding psychopharmacologic interventions must be interpreted and applied to patient care. By understanding the newest available data, geriatric psychiatrists will be well-positioned to expand their role as consultants to primary care and long-term care and as educators to the community. Dr. Jackson reviews how traditional approaches in the treatment of Alzheimer’s disease have focused on improving cognitive status by increasing the levels of acetylcholine in the synapse. However, as newer cholinesterase inhibitors have moved through clinical trials, it has become apparent that this simplistic understanding does not explain the unanticipated behavioral benefits seen from these “cognitive enhancers” and that more data is needed. Dr. Reichman highlights other treatment modalities including Ginkgo biloba, vitamin E, selegiline, estrogen, and nonsteroidal anti-inflammatories. The data for newer nicotinic-mediated medications, including galantamine, are also reviewed where Dr. Reichman explores the possibility that nicotinic modulating activity may add to the standard clinical therapeutic benefits. Dr. Schneider presents new analyses of antidementia drug utilization by physicians. By examining more than 5 years of data (IMS America, Inc.), he will describe secular trends in prescribing patterns with the available cholinesterase inhibitors, tacrine, donepezil, and rivastigmine. These analyses describe types of physicians prescribing, indications for prescribing, dosages, number of new prescriptions, and refills. The extent of polypharmacy and comorbid conditions are evaluated, as well as recent effects of the increase in vitamin E usage. For example, preliminary analyses indicate that the median length of a prescription for donepezil is 16 weeks, with a very low proportion of refills. The reasons for this apparently short duration will be further analyzed in the light of existing efficacy data. The
24
T
raditional approaches in treating Alzheimer’s patients focused on behavior management until the advent of acetylcholine enhancers. With the advent of tacrine, treatment of cognitive impairment became possible. Unfortunately, there were numerous problems with side effects, a need for liver monitoring, and the frequent dosing schedule. This presentation briefly reviews the effectiveness of tacrine and the tolerability profile. Donepezil has become the preferred treatment intervention for Alzheimer’s patients, primarily due to the improved side-effect profile and once-a-day dosing. Data are reviewed on donepzil’s ability to delay progression rather than to significantly improve most patients’ cognitive capacity.
NEW HORIZONS IN PHARMACOLOGIC INTERVENTIONS: WHERE ARE WE GOING? William E. Reichman, M.D.
I
n recent years we have seen the introduction of newergeneration cholinesterase inhibitors for the treatment of the cognitive deficits of AD. Donepezil, rivastigmine, metrifonate, and galantamine offer practical as well as theoretical advantages over earlier therapies. While such drugs offer the promise of modest degrees of cognition enhancement and possibly neuroprotection, their potentially beneficial psychotropic properties are also being increasingly recognized. Importantly, the standard pharmacotherapy of AD may also include emerging therapies for neuroprotection such as vitamin E, selegeline, ginko biloba, novel antiinflammatory compounds such as the COXII inhibitors, and estrogens. Anti-amyloid strategies as well as neural transplantation and gene therapy loom on the horizon. This talk focuses on the evolving spectrum of these approaches with a review of the most up-to-date research data available. The promise of these new techniques for the clinical treatment of AD are highlighted.
Am J Geriatr Psychiatry Supplement, Fall 1999