Noradrenergic Activity is Associated with Response to Pindolol in Aggressive Alzheimer’s Disease Patients
Identifieur interne : 001704 ( Istex/Corpus ); précédent : 001703; suivant : 001705Noradrenergic Activity is Associated with Response to Pindolol in Aggressive Alzheimer’s Disease Patients
Auteurs : Nathan Herrmann ; Krista L. Lanctôt ; Goran Eryavec ; Lyla R. KhanSource :
- Journal of Psychopharmacology [ 0269-8811 ] ; 2004-06.
Abstract
Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer’s disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 μg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.
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DOI: 10.1177/0269881104042625
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Noradrenergic Activity is Associated with Response to Pindolol in Aggressive Alzheimer’s Disease Patients</title><author wicri:is="90%"><name sortKey="Herrmann, Nathan" sort="Herrmann, Nathan" uniqKey="Herrmann N" first="Nathan" last="Herrmann">Nathan Herrmann</name><affiliation><mods:affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada.,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: nathan.herrmann@sw.ca</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Lanctot, Krista L" sort="Lanctot, Krista L" uniqKey="Lanctot K" first="Krista L." last="Lanctôt">Krista L. 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Lanctôt</name><affiliation><mods:affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada.</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Eryavec, Goran" sort="Eryavec, Goran" uniqKey="Eryavec G" first="Goran" last="Eryavec">Goran Eryavec</name><affiliation><mods:affiliation>Department of Psychiatry, North York General Hospital and University of Toronto, Toronto, Ontario, Canada.</mods:affiliation></affiliation></author><author wicri:is="90%"><name sortKey="Khan, Lyla R" sort="Khan, Lyla R" uniqKey="Khan L" first="Lyla R." last="Khan">Lyla R. Khan</name><affiliation><mods:affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Psychopharmacology</title><idno type="ISSN">0269-8811</idno><idno type="eISSN">1461-7285</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="2004-06">2004-06</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="215">215</biblScope><biblScope unit="page" to="220">220</biblScope></imprint><idno type="ISSN">0269-8811</idno></series><idno type="istex">791DC44A14721B55E2E5D97BA192411EF47E68B9</idno><idno type="DOI">10.1177/0269881104042625</idno><idno type="ArticleID">10.1177_0269881104042625</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0269-8811</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer’s disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 μg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.</div></front></TEI><istex><corpusName>sage</corpusName><author><json:item><name>Nathan Herrmann</name><affiliations><json:string>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada.,</json:string><json:string>E-mail: nathan.herrmann@sw.ca</json:string></affiliations></json:item><json:item><name>Krista L. 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Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. 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Pharmacology, University of Toronto, Toronto, Ontario, Canada.</affiliation></author><author xml:id="author-3"><persName><forename type="first">Goran</forename><surname>Eryavec</surname></persName><affiliation>Department of Psychiatry, North York General Hospital and University of Toronto, Toronto, Ontario, Canada.</affiliation></author><author xml:id="author-4"><persName><forename type="first">Lyla R.</forename><surname>Khan</surname></persName><affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada.</affiliation></author></analytic><monogr><title level="j">Journal of Psychopharmacology</title><idno type="pISSN">0269-8811</idno><idno type="eISSN">1461-7285</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="2004-06"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="215">215</biblScope><biblScope unit="page" to="220">220</biblScope></imprint></monogr><idno type="istex">791DC44A14721B55E2E5D97BA192411EF47E68B9</idno><idno type="DOI">10.1177/0269881104042625</idno><idno type="ArticleID">10.1177_0269881104042625</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer’s disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 μg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>aggression</term></item><item><term>Alzheimer’s disease</term></item><item><term>behavioural and psychological symptoms of dementia</term></item><item><term>neurochemical pathology</term></item><item><term>norepinephrine</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/791DC44A14721B55E2E5D97BA192411EF47E68B9/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus sage not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article" dtd-version="2.3" xml:lang="EN"><front><journal-meta><journal-id journal-id-type="hwp">spjop</journal-id><journal-id journal-id-type="publisher-id">JOP</journal-id><journal-title>Journal of Psychopharmacology</journal-title><issn pub-type="ppub">0269-8811</issn><publisher><publisher-name>Sage Publications</publisher-name><publisher-loc>Sage CA: Thousand Oaks, CA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1177/0269881104042625</article-id><article-id pub-id-type="publisher-id">10.1177_0269881104042625</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Noradrenergic Activity is Associated with Response to Pindolol in Aggressive Alzheimer’s Disease Patients</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Herrmann</surname><given-names>Nathan</given-names></name><aff>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada., <email xlink:type="simple">nathan.herrmann@sw.ca</email></aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Lanctôt</surname><given-names>Krista L.</given-names></name><aff>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada.</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Eryavec</surname><given-names>Goran</given-names></name><aff>Department of Psychiatry, North York General Hospital and University of Toronto, Toronto, Ontario, Canada.</aff></contrib></contrib-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Khan</surname><given-names>Lyla R.</given-names></name><aff>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada.</aff></contrib></contrib-group><pub-date pub-type="ppub"><month>06</month><year>2004</year></pub-date><volume>18</volume><issue>2</issue><fpage>215</fpage><lpage>220</lpage><abstract><p>Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer’s disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 μg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired <italic>t</italic> = -2.5, <italic>p</italic> = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (<italic>r</italic> = 0.91, <italic>F</italic> = 10.5, <italic>p</italic> = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.</p></abstract><kwd-group><kwd>aggression</kwd><kwd>Alzheimer’s disease</kwd><kwd>behavioural and psychological symptoms of dementia</kwd><kwd>neurochemical pathology</kwd><kwd>norepinephrine</kwd></kwd-group><custom-meta-wrap><custom-meta xlink:type="simple"><meta-name>sagemeta-type</meta-name><meta-value>Journal Article</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>search-text</meta-name><meta-value> Introduction Behavioural and psychological symptoms of dementia (BPSD) are common, serious problems that impair quality of life for patients and their caregivers, lead to premature institutionalization and have significant cost implications (Herrmann, 2001). Although there are numerous recommended treatments available, therapeutic benefits are often modest at best, and some investigators continue to ques- tion whether current interventions are beneficial at all (Teri et al., 2000). Hampering the development of effective therapeutic tech- niques is the heterogeneity of BPSD and a lack of data on their underlying neurobiology (Herrmann and Lanctôt, 1997). Attempts have been made to characterize various behaviours based on their phenomenology, neurotransmitter changes, neuropathology, neuro- imaging and neuropyschological correlates. One of the best studied neurotransmitters believed to be associated with BPSD is serotonin, with disruptions hypothesized to have significant impli- cations for behaviours such as agitation, aggression and depression (Lanctôt et al., 2001). Of all BPSD, aggression is one of the most important, and has been identified as the most serious problem faced by caregivers (Rabins et al., 1982). Aggression has been associated with increased caregiver burden (Rabins et al., 1982; Nygaard, 1988; Keene et al., 1999), institutionalization (Steele et al., 1990; Cohen Journal of Psychopharmacology 18(2) (2004) 215220 © 2004 British Association for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, London, Thousand Oaks, CA and New Delhi 10.1177/0269881104042625 Noradrenergic activity is associated with response to pindolol in aggressive Alzheimer's disease patients Nathan Herrmann Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada. Krista L. Lanctôt Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada. Goran Eryavec Department of Psychiatry, North York General Hospital and University of Toronto, Toronto, Ontario, Canada. Lyla R. Khan Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada. Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer's disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 µg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = 2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy. Keywords aggression, Alzheimer's disease, behavioural and psychological symptoms of dementia, neurochemical pathology, norepinephrine Abstract Corresponding author: Dr N. Herrmann, Department of Psychiatry, Sunnybrook and Women's, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. Email: nathan.herrmann@sw.ca Original papers et al., 1993), use of physical restraints (Evans and Strumpf, 1989), use of psychoactive medications (Keene et al., 1999), falls (Marx et al., 1990), weight loss (Merriam et al., 1988) and a more rapid decline (Lopez et al., 1999). Serotonergic dysfunction has been associated with aggression in Alzheimer's disease (AD), and sero- tonergic therapies with selective serotonin reuptake inhibitors have been described (Pollock et al., 2002), although many patients fail to demonstrate a robust clinical response (Lanctôt et al., 2002). Much less data are available on the role of noradrenergic (NE) dysfunction and NE therapies for aggression in AD. There are significant structural and functional changes in the NE system in AD (Storga et al., 1996; Hoogendijk et al., 1999; Matthews et al., 2002). NE dysfunction has also been implicated in aggression in animal models and some non-demented patient populations (Herrmann et al., 2004). Although there are only two studies that have linked NE dysfunction with aggression in AD, both were post-mortem studies (Russo-Neustadt and Cotman, 1997; Matthews et al., 2002). There have also been a small num- ber of case series and controlled trials of NE therapy for aggression and agitation. These have included controlled studies of the -blockers propranolol and pindolol in mixed diagnoses dementia patients with various BPSD, with the largest of these studies including only 15 subjects (Greendyke and Kanter, 1986; Greendyke et al., 1986, 1989). We attempted to study the correlates of aggression response to NE therapy with pindolol in AD patients. We hypothesized that a blunted growth hormone (GH) response to clonidine challenge (a marker of central NE activity) would be associated with greater therapeutic effectiveness. Methods Subjects were residents of two long-term care facilities associated with university affiliated general hospitals. The Research Ethics Board of each hospital approved the study. Written informed con- sent was obtained from the legal substitute decision-makers for each patient after a complete discussion of the study. Each subject received a comprehensive diagnostic assessment, including physical, neurological and psychiatric examinations. All subjects met criteria for NINCDSADRDA probable AD of at least 1 year's duration. Subjects were > 55 years of age and scored < 24 on a Mini-Mental State Examination (MMSE) (Folstein et al., 1975). Subjects were excluded if they had clinical or labora- tory evidence of a significant medical illness, an Ischemic Scale Score > 3 (Hachinski et al., 1975), or neuroimaging data that could not be interpreted as being consistent with the diagnosis of AD. Subjects were also excluded if there was evidence of significant cardiovascular disease or hypertension (> 160/100 mmHg). To be included in the study, subjects had to have significant BPSD with Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) scores 8. Subjects were excluded if there was a premorbid or current psychiatric diagnosis including depression. Subjects underwent a placebo washout of all psychotropic drugs based on a minimum of five half-lives of the psychotropic drug utilized. Following washout and baseline assessments, subjects underwent a clonidine challenge test. Subjects were NPO after midnight before testing and were provided with juice and light snacks during the testing to prevent dehydration and hypo- glycemia, both of which can affect GH secretion. Subjects were awake and recumbent throughout the procedure as sleep, distress and exercise alter GH secretion. Two blood samples were obtained for baseline GH concentration. Clonidine 5 µg/kg was adminis- tered orally. Two blood samples taken at 60 and 90 min post- clonidine were drawn, and blood pressure was measured every 30 min. GH concentrations were determined by radioimmunoassay. Following the clonidine challenge, subjects were randomized to receive pindolol 2.5 mg p.o., b.i.d. or an identical placebo capsule. After 3 days, the study drugs were increased to 5 mg b.i.d. for 3 days, then 10 mg b.i.d. for 4 days followed by 20 mg b.i.d. Subjects received a maximum dose for 29 days followed by an identical tapering schedule. Subjects then received 1 week of single-blind placebo therapy after which they were crossed-over to receive the other treatment. Patients were assessed at five visits: screening, following psy- choactive washout and just prior to clonidine challenge (baseline), following treatment phase I (week 7), following placebo washout (week 8), and following treatment phase II (week 15). At each visit behaviour, cognition, medication tolerability and cardiovascular status were assessed blind to treatment. Overall psychopathology was assessed with the NPI. The primary outcome measure was the retrospective Overt Aggression Scale (r-OAS) (Sorgi et al., 1991), which was chosen specifically because it provides a more detailed description of aggressive behaviours compared to the NPI and has been used in previous studies of -blockers for aggression (Greendyke et al., 1989). Cognition was measured with the MMSE and depression was assessed with the Cornell Scale for Depression in Dementia (Alexopoulos et al., 1988). Pindolol was the only active drug used to manage BPSD during the study. There was the provision for the administration of the short-acting sedative hypnotic lorazepam to be used, if needed, but this could not be used more than four times per week. Primary analyses were performed to determine if aggression and/or clonidine challenge results, among other factors, were pre- dictors of response. A 'treatment responder' was defined as an improvement on r-OAS score following pindolol therapy com- pared to placebo treatments (i.e. score at the end of placebo treat- ment minus score at the end of pindolol treatment). Multiple regression analyses were performed to determine predictors of response. GH response was calculated as the maximum change from baseline (difference between peak concentration post- clonidine and mean of the two baseline values). Baseline aggres- sion (r-OAS score), GH response, age, gender and MMSE were entered into a regression analysis. Results were also examined for a treatment-order effect. Results Twenty-eight patients who met inclusion criteria were referred or identified. Consent to participate was obtained from substitute decision-makers for 15 of these patients and the remainder refused 216 Noradrenergic activity and response to pindolol to consent to participate. Baseline characteristics are reported in Table 1. Subjects were aged 81.5 ± 5.5 years with average MMSE scores of 3.3 ± 4.6 and NPI scores of 30.6 ± 14.6. Mean baseline r-OAS was 28.4 ± 22.4 (range 083). Before washout, four subjects were withdrawn from antipsychotics, one from an antidepressant, and three from benzodiazepines. There were four dropouts and 11 completers. One subject dropped out 10 days into treatment phase I and a second subject dropped out 5 days into treatment phase II, both due to lack of efficacy. Both of these subjects were receiving pindolol at the time of dropout. Two other subjects dropped out at 6 and 13 days into treatment phase I: one due to withdrawal of consent, and one as a result of hospitalization secondary to viral gastroenteritis. Both subjects were receiving pindolol at the time of dropout. Five of 11 completers (45%) (33% of intention to treat) had decreased total r-OAS scores following pindolol compared to placebo. Compared with placebo treatment, pindolol treatment resulted in significant improvement on the r-OAS verbal aggres- sion subscale (paired t = 2.5, p = 0.03) but no significant change in total r-OAS (Table 2). When baseline aggression, GH response, age, gender and MMSE were entered into a regression analysis, higher baseline r-OAS, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (F = 10.5, p = 0.006) (Table 3). Clonidine dose (t = 0.57, p = 0.59) and plasma clonidine concentrations (t = 1.1, p = 0.33, 60 min; t = 0.05, p = 0.96, 90 min) did not differ between responders and non-responders. Comparing mean change on r-OAS by order of treatment showed no evidence of an order effect (t = 0.07, p = 0.94). There were no differences between proportions of patients who used psychotropics immedi- ately before washout in responders versus non-responders or those with a blunted GH response versus those without (Fisher's exact tests, both p = 0.99). There were no differences in use of lorazepam between treatment phases. There were nine reported adverse events in eight subjects. Placebo-treated subjects experienced a skin ulcer, a fall, an episode of haematuria, a pruritic skin rash, a skin abscess and an episode of hypotension. Pindolol-treated subjects experienced an episode of leg pain, sedation and hypotension. For all pindolol-treated subjects, the average blood pressure changes from pre to post-treatment were 11.4 ± 15.3 mmHg systolic and 3.9 ± 7.1 mmHg diastolic. Discussion This study is the first randomized placebo controlled trial of pin- dolol therapy in AD to examine predictors of aggression response. Subjects with more aggression (higher baseline r-OAS scores), less cognitive impairment (higher MMSE scores) and a blunted GH response to clonidine challenge demonstrated greater reductions in Noradrenergic activity and response to pindolol 217 Table 1 Subjects (n = 15) Characteristic Age 81.5 ± 5.5 (7289) Male : female 11 : 4 MMSE 3.3 ± 4.2 (013) Baseline NPI total 30.6 ± 14.6 (963) Baseline NPI aggression 8.6 ± 3.6 (212) Baseline r-OAS 28.4 ± 22.4 (083) Baseline GH (ng/ml) 1.5 ± 2.1 (0.158.5) Maximum change from baseline (ng/ml) 0.08 ± 6.5 (14.517.4) Data are mean ± SD (range). Table 2 Treatment responsea Baseline (mean ± SD) Change scores (mean ± SD)b r-OAS total 23.36 ± 16.60 1.36 ± 19.82 r-OAS physical aggression objects 4.73 ± 5.08 0.27 ± 4.21 r-OAS physical aggression self 2.18 ± 4.05 2.18 ± 5.55 r-OAS physical aggression others 11.00 ± 10.79 1.09 ± 13.66 r-OAS verbal aggression 5.45 ± 7.12 2.18 ± 2.89 NPI total 28.18 ± 12.42 0.91 ± 9.30 NPI aggression 8.18 ± 3.84 1.73 ± 4.88 an = 11 completers. bchange score = drug placebo. Table 3 Regression analysis showing variables predicting response to pindolol on rOAS Variable Beta (parameter estimate) Standard error of beta p GH response (maximum change from baseline) 1.417 0.421 0.012 MMSE after initial washout 1.975 0.726 0.030 r-OAS aggression after initial washout 0.644 0.194 0.013 (Constant) 19.664 5.974 0.013 The equation is: rOAS = 19.6641.975 × MMSE + 1.417 × GH response 0.644 × aggression. aggression following pindolol compared to placebo therapy. The GH response to clonidine challenge has been used extensively in psychiatry as a measure of central NE activity. GH response to clonidine reflects post-synaptic 2 sensitivity. Blunted GH response, suggesting NE overactivity, has been demonstrated in normal ageing (Gil-Ad et al., 1984), depression (Siever and Uhde, 1984; Valdivieso et al., 1996), generalized anxiety disorder (Nutt, 2001) and AD (Gilles et al., 1989). A blunted GH response has been viewed as either a reflection of post-synaptic 2 adrenergic receptor down regulation in response to NE overactivity (Siever and Uhde, 1984; Uhde et al., 1986), or a reduced ability of locus ceruleus (LC) neurones to release NE (Charney and Heninger, 1986). Of these two possiblities, the latter is most likely because loss of LC neurones in AD is well established (Perry et al., 1981; Mann et al., 1982; Iversen et al., 1983; Mann et al., 1984; Moll et al., 1990; Miller et al., 1999; Matthews et al., 2002; Zarow et al., 2003). More importantly, data from two post-mortem studies (Russo-Neustadt and Cotman, 1997; Matthews et al., 2002) sug- gest that greater NE neurone loss in the LC, in the presence of pre- served post-synaptic NE receptors, is associated with aggressive behaviours in AD. Thus, the association of a blunted response and higher baseline aggression with better response to pindolol in this study appears consistent with the post-mortem data. Furthermore, in a post-mortem study by performed Russo-Neustadt and Cotman (1997), 1 and 2 adrenergic receptors in the cerebellar cortex showed significant increases in concentration in aggressive AD subjects compared to both non-aggressive AD subjects and age- matched controls. The cerebellum has been postulated to modulate aggression and mood based on neurosurgical manipulation studies (Berman, 1997), lesion studies (Heath, 1977; Schmahmann and Sherman, 1998; Levisohn et al., 2000) and functional imaging studies (Berman, 1997). This suggests another possible explana- tion for the association of increased aggression and pindolol response (i.e. modulation of increased -adrenergic receptors in the cerebellar cortex). In this study, pindolol therapy demonstrated very modest bene- fits. Although it is possible pindolol may not be as effective as other -blockers such as propranolol, previous studies have con- cluded that pindolol is effective (Greendyke and Kanter, 1986; Greendyke et al., 1989). However, it is interesting to note that, in one double-blind randomized controlled trial with organic brain syndrome patients, although six of 13 patients were rated as improved with lower r-OAS scores, none of the rating scales scores, including the r-OAS, demonstrated statistically significant improvements (Greendyke et al., 1989). The authors suggested that this may be due to the low absolute frequency of aggressive events, which makes it difficult to demonstrate improvement in aggression using these scales in the relatively short time frame of a random- ized controlled trial. These authors also suggest that there might be hetereogeneity of response, and that it was their impression that patients with more severe brain damage showed the greatest improvement with pindolol. We believe that hetereogeneity of response is the most likely reason for the modest efficacy of pindolol, emphasizing the need to search for factors that would predict response for the individual patient. This study was not designed as an efficacy trial and therefore conclusions about the efficacy of pindolol therapy for aggression in AD must be limited due to the small sample size and lack of power. Other limitations include the cross-over design and the short treatment phases. While some controlled trials of -blockers in mixed patient populations have utilized lengthy treatment phases, at least one study of pindolol in organic brain syndrome patients noted rapid onset of action with beneficial effects occurring within the first 2 weeks of treatment (Greendyke and Kanter, 1986). Furthermore, we have previously argued that any medication pre- scribed for BPSD, especially with aggression as a target symptom, would be of limited value if significant improvement could not be demonstrated within 1 month of initiation (Lanctôt et al., 2002). It is unlikely that the dose of pindolol played a role in the modest response rate, even though the maximum dose used in this study (40 mg/day) would be at the lower range of maximum doses used in previous studies. The subjects in this study were far older and frailer compared to previous studies, and at least one open trial has suggested that even small doses of -blockers are effective at reducing agitation and aggression in elderly demented individuals (Shankle et al., 1995). Finally, it is important to note that pindolol has 5-HT1A antagonist properties (Blier and Bergeron, 1998), making it less of a specific NE therapy compared to propranolol. However, the intrinsic sympathomimetic activity of pindolol makes it a better choice for elderly patients, potentially causing less bradycardia and hypotension. While the 5-HT1A effects of pindolol may contribute to efficacy and limit the ability to link efficacy exclusively with NE blockade, the fact that clonidine chal- lenge predicted response to pindolol suggests that the effects of NE were at least partially responsible for efficacy. 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Alzheimer’s Disease Patients</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Noradrenergic Activity is Associated with Response to Pindolol in Aggressive Alzheimer’s Disease Patients</title></titleInfo><name type="personal"><namePart type="given">Nathan</namePart><namePart type="family">Herrmann</namePart><affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada.,</affiliation><affiliation>E-mail: nathan.herrmann@sw.ca</affiliation></name><name type="personal"><namePart type="given">Krista L.</namePart><namePart type="family">Lanctôt</namePart><affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada.</affiliation></name><name type="personal"><namePart type="given">Goran</namePart><namePart type="family">Eryavec</namePart><affiliation>Department of Psychiatry, North York General Hospital and University of Toronto, Toronto, Ontario, Canada.</affiliation></name><name type="personal"><namePart type="given">Lyla R.</namePart><namePart type="family">Khan</namePart><affiliation>Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada.</affiliation></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Sage Publications</publisher><place><placeTerm type="text">Sage CA: Thousand Oaks, CA</placeTerm></place><dateIssued encoding="w3cdtf">2004-06</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer’s disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 ± 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 ± 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 μg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.</abstract><subject><genre>keywords</genre><topic>aggression</topic><topic>Alzheimer’s disease</topic><topic>behavioural and psychological symptoms of dementia</topic><topic>neurochemical pathology</topic><topic>norepinephrine</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Psychopharmacology</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0269-8811</identifier><identifier type="eISSN">1461-7285</identifier><identifier type="PublisherID">JOP</identifier><identifier type="PublisherID-hwp">spjop</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>2</number></detail><extent unit="pages"><start>215</start><end>220</end></extent></part></relatedItem><identifier type="istex">791DC44A14721B55E2E5D97BA192411EF47E68B9</identifier><identifier type="DOI">10.1177/0269881104042625</identifier><identifier type="ArticleID">10.1177_0269881104042625</identifier><recordInfo><recordContentSource>SAGE</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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