Biomedical subjects

R A Sweet

Publications and source records attributed to R A Sweet.

At least 19 recordsLinked to original sources

PubMed2006

Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease.

OBJECTIVE: To determine the relationship between major depression and the presence of Lewy bodies (LBs) in patients with Alzheimer disease (AD). METHODS: The authors examined the presence of major depression in 267 pathologically diagnosed AD cases with Mini-Mental State Examination (MMSE) scores >9. LBs were identified in 142 (53%) patients using alpha-synuclein immunohistochemistry. Subjects were classified according to the Consensus Guidelines for the Clinical and Pathologic Diagnosis of Dementia with LB: 1 to 2 (n = 21), 3 to 6 (n = 26), and 7 to 10 (n = 69). Twenty-six patients had LB only in the amygdala. All cases with LB scores 7 to 10 (or cortical) had amygdala LBs. The association between LBs and major depression was examined with logistic regression analyses, controlled for age at study entry, education level, MMSE scores, antidepressant use, follow-up time, and the presence of cerebrovascular disease. RESULTS: Major depression was present in 11 (9%) AD alone cases, and in 25 (18%) of the AD + LBs cases; amygdala: 8 (31%), scores 1 to 2: 1 (5%), scores 3 to 6: 3 (11.5%), and scores 7 to 10: 13 (14%). Major depression was associated with LBs, in general (relative risk [RR] = 3.06, 95% CI: 1.25 to 7.46), with amygdala only LBs (RR = 8.56 (95% CI: 1.83 to 40.3), and with LB scores 7 to 10 (RR = 3.83, 95% CI: 1.33 to 11.0). There was an association between all amygdala LBs cases (amygdala only LBs + LB scores 7 to 10) and major depression (RR = 4.77, 95% CI: 1.78 to 12.7), but no association was noted between LBs and depression in the absence of amygdala LBs (RR = 0.96, 95% CI: 0.46 to 1.06). CONCLUSION: Lewy bodies (LBs) in the amygdala and in cortical areas increase the risk for major depression in Alzheimer disease. What is common in these two groups is the presence of LBs in the amygdala. That is, all of the cases with cortical LBs also had LBs in the amygdala, making this region the critical area for the development of depression.

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PubMed2005

Regional specificity of chandelier neuron axon terminal alterations in schizophrenia.

BACKGROUND: The axon terminals of GABAergic chandelier cells form linear arrays, termed cartridges, that synapse on the axon initial segment of neocortical pyramidal cells. These cartridges are immunoreactive for the GABA membrane transporter-1, and the density of GABA membrane transporter-1-immunoreactive cartridges in the prefrontal cortex has been reported to be reduced in schizophrenia. The goal of this study was to determine if reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in schizophrenia are restricted to the prefrontal cortex. METHODS: Relative GABA membrane transporter-1-immunoreactive cartridge density was determined in auditory association area 42, a region previously implicated in the pathophysiology of schizophrenia, in 14 matched pairs of subjects with schizophrenia and normal comparison subjects. The results were compared with similar data from prefrontal area 46 in the same subjects. RESULTS: Mean GABA membrane transporter-1-immunoreactive cartridge density in area 42 was decreased by 9.8% in layers II-IIIa, and by 11.9% in layer VI in subjects with schizophrenia, although these differences did not achieve statistical significance. However, the magnitude of the reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in area 42 of the subjects with schizophrenia was not significantly smaller than those in area 46. CONCLUSIONS: In subjects with schizophrenia, alterations in chandelier neuron axon cartridges appear to be more marked in the prefrontal cortex than in another cortical region implicated in the illness, although such changes might not be restricted to the prefrontal cortex.

Adult↗

PubMed2005

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease.

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

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PubMed2003

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype.

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses.

Alzheimer Disease↗

PubMed2002

Linkage analysis of Alzheimer disease with psychosis.

Although a portion of risk for late-onset AD (LOAD) is attributable to APOE, the search for other loci is ongoing. The authors hypothesize that psychotic symptoms with LOAD (LOAD+P) identify a potentially more etiologically homogeneous form of AD. Linkage analysis of families with LOAD+P identified one significant and several suggestive novel linkage signals, which bolsters the conjecture of greater etiologic homogeneity.

Alzheimer Disease↗

PubMed2002

Increased familial risk of the psychotic phenotype of Alzheimer disease.

BACKGROUND: Psychotic symptoms in patients with AD (AD with psychosis [AD+P]) define a phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. OBJECTIVE: To determine if AD+P aggregates within families. METHODS: Case-control study of AD+P frequency in 461 siblings of 371 probands diagnosed with AD. All siblings were ascertained as part of a genetic investigation and also were diagnosed with AD. Statistical analysis used Generalized Estimating Equations to adjust for clustering within families. RESULTS: AD+P in probands was associated with a significantly increased risk for AD+P in family members (OR, 2.41; 95% CI 1.46-4.0; p = 0.0006). The correlation among siblings for AD+P status was modest: 0.16. CONCLUSION: AD+P demonstrates familial aggregation. Further studies are required to investigate a possible genetic basis of AD+P.

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PubMed2002

The establishment of a brain bank for the study of late-life depression: a feasibility study of factors facilitating consent.

BACKGROUND: Studies of postmortem brain tissue are advancing the understanding of the pathophysiology of major depressive disorder (MDD). The nature and quality of subject samples, however, limit their applicability to late-life MDD. OBJECTIVE: To examine the feasibility of establishing a brain bank for late-life MDD, and identify clinical, demographic, and procedural factors that might facilitate subject enrollment. METHODS: Elderly subjects participating in clinical trials associated with the Mental Health Intervention Research Center for Late-Life Mood Disorders (MHIRC/LLMD) at the University of Pittsburgh were approached by clinical research staff for consent to future brain-only autopsy. Subjects who consented to participation were compared with those who refused participation on demographic and clinical variables. MHIRC/LLMD clinical research staff were interviewed to determine factors that may have facilitated or hindered the consent process and reasons for subject consent or refusal. RESULTS: Eighty out of 242 subjects (33%) subjects approached for participation in the brain bank provided consent. Consent to participate was associated with higher level of education and with lower Mini-Mental State Examination score. Several factors facilitating and hindering the consent process were identified. CONCLUSION: We provide preliminary evidence for the feasibility of establishing a brain bank for the study of late-life MDD. Future efforts may be guided by the factors identified as facilitating the consent process, especially the inclusion of family in the consent process.

Journal Article↗

PubMed2001

Alterations of striatal dopamine receptor binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis.

BACKGROUND: Lewy bodies (LB) are present in at least 20% to 30% of persons with Alzheimer disease (AD) and contribute to the risk of psychosis and to excess cognitive burden. OBJECTIVE: To determine whether altered striatal dopamine receptor binding is associated with LB and psychosis in AD. DESIGN: Postmortem case control. SETTING: Alzheimer's Disease Research Center at the University of Pittsburgh (Pa). PARTICIPANTS: Consecutive cases from the Alzheimer's Disease Research Center brain bank, neuroleptic free for at least 1 month prior to death, with neuropathologic diagnoses of AD with LB (AD + LB, n = 14), AD without LB (AD, n = 13), or normal brains (n = 8). MAIN OUTCOME MEASURES: Dopamine D1, D2, and D3 receptor densities, and affinities as determined by selective saturation binding studies in striatal tissue. RESULTS: Subjects with AD + LB, compared with those with AD, demonstrated increased D1 receptor density and decreased D2 and D3 receptor density. D3 receptor density was selectively increased, however, in AD subjects with a history of psychosis, independent of the presence or absence of LB. The effect of neuroleptic treatment on D3 binding was further examined in an additional group of subjects who had received neuroleptics near the time of death. Neuroleptic treatment reduced D3 affinity with no effect on D3 density. CONCLUSIONS: Alzheimer disease with LB is associated with selective alterations in dopamine receptor density, which may contribute to the distinct clinical profile of this group. The D3 receptor may be an important target of neuroleptic treatment of psychosis in AD.

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PubMed2001

The 5-HTTPRS/L polymorphism and aggressive behavior in Alzheimer disease.

BACKGROUND: Aggressive behavior in Alzheimer disease (AD) has been linked to dysfunction of serotonin neurotransmission. Homozygosity for the long variant (*L) of an identified biallelic polymorphism of the serotonin transporter promoter region (5-HTTPR) is associated with increased expression of the transporter protein and increased speed of response to serotonin reuptake inhibitor treatment. OBJECTIVE: To determine whether the *L/*L genotype and the *L allele are associated with an increased risk of aggressive symptoms in patients with AD. DESIGN: Case-control study. SETTING: University hospital geriatric psychiatry inpatient program and Alzheimer disease research center. SUBJECTS: Fifty-eight patients with AD with a history of aggressive behavior and 79 never-aggressive patients with AD with comparable severity of cognitive impairment. MAIN OUTCOME MEASURES: The 5-HTTPR genotype and allele frequency. RESULTS: The *L/*L genotype was significantly associated with aggression in patients with AD (odds ratio, 2.8; 95% confidence interval, 1.2-6.5). Similar results were obtained for *L allele frequency. CONCLUSION: The 5-HTTPR*L allele and *L/*L genotype may predispose patients with AD to develop aggressive behavior.

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PubMed2001

The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease.

BACKGROUND: Psychotic symptoms in subjects with Alzheimer disease (AD+psychosis, AD+P) are a marker for a distinct phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. We recently found that AD subjects homozygous for long alleles (l) of an insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTPR) had elevated rates of aggressive behavior. OBJECTIVE: To examine whether the 5-HTTPR ll genotype confers an increased risk of AD+P, and of the combined AD+P/aggressive phenotype. METHODS: The 5-HTTPR genotype was determined in 332 subjects diagnosed with possible or probable AD. All subjects received structured psychiatric assessments and were categorized with regard to their history of aggressive behaviors and psychotic symptoms. RESULTS: Consistent with other reports, AD+P was associated with a significant increased risk for aggressive behavior. AD+P and aggression were both significantly associated with 5-HTTPR ll genotype and with an increased l allele frequency. Subjects with the combined behavioral phenotype (AD+P and aggressive behavior) had the highest rate of ll genotype and highest l allele frequency. CONCLUSION: The 5-HTTPR l allele appears to confer risk for the combined AD+P/aggressive phenotype. Confirmation of this association in a similar behaviorally well-characterized independent sample is needed.

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PubMed2001

Antipsychotic radioreceptor assay: a modification identifying selective receptor effects.

Radioreceptor assays offer the advantage of a single assay that can assess uniform exposure to multiple chemical compounds. The advent of atypical antipsychotic agents has led to new awareness of the multiple receptor subtypes through which antipsychotic agents may exert their effects, and a renewed interest in comparative drug trials of antipsychotics. The objective of this study was to show the development and validation of antipsychotic radioreceptor assays using clonal cell lines stably expressing isolated human receptors. Model assays were developed using the dopamine(2) (D(2)) and D(4) receptors. D(2) and D(4) activities measured by radioreceptor assay in plasma of antipsychotic-treated subjects were highly correlated with high-performance liquid chromatography determinations of antipsychotic concentrations. Similarly, for a variety of typical and atypical antipsychotic agents, the quotients of D(4)/D(2) activity in plasma of antipsychotic-treated subjects were highly correlated with the quotients of D(4)/D(2) affinities of these agents. Valid receptor-selective antipsychotic assays can be established and may have utility for dissecting the in vivo activity of atypical antipsychotics in relation to specific outcomes in clinical trials.

Antipsychotic Agents↗

PubMed2001

A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life.

OBJECTIVE: To conduct the first randomized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression. METHOD: The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features (DSM-III-R criteria). Patients were started openly on nortriptyline treatment titrated to therapeutic levels. They were then randomly assigned under double-blind conditions to addition of perphenazine or placebo. Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression (HAM-D) and the Brief Psychiatric Rating Scale (BPRS); side effects were assessed with the Geriatric Movement Disorder Assessment. RESULTS: Both treatments were well tolerated. Of the 36 randomly assigned patients, 2 (1 in each group) dropped out due to treatment-related adverse effects. Four additional patients dropped out for administrative reasons. Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine (N = 14) or placebo (N = 16) for at least 2 weeks (median = 9 weeks). There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D, the BPRS, its psychoticism subscale, or any side effects measure. Rates of response (defined as resolution of both depression and psychosis) did not differ significantly in the 2 groups (nortriptyline-plus-perphenazine group, 50% vs. nortriptyline-plus-placebo group, 44%). CONCLUSION: When treating older patients with psychotic depression, the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy. This finding supports existing data suggesting that the pathophysiology (and thus the required treatment) of psychotic depression may be different early and late in life.

Affective Disorders, Psychotic↗

PubMed2001

A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients.

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.

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PubMed2000

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

OBJECTIVE: To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. BACKGROUND: Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. RESULTS: The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. CONCLUSION: Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

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PubMed2000

Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades: II.

OBJECTIVE: To describe the experience of a research clinic diagnosing possible AD during the last two decades. BACKGROUND: The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for possible AD are generally used to indicate that a patient has AD in association with another disease process that could by itself cause dementia. There are no studies describing how these criteria should be applied, and there are no descriptions of functional and cognitive progression or survival in possible AD. METHODS: The authors examined the clinical characteristics of 267 patients diagnosed with possible AD at the AD Research Center of Pittsburgh from 1983 to 2000 and the likelihood of arriving at four endpoints: Mini-Mental State Examination score of </= 9, Blessed Dementia Rating Scale for activities of daily living score of >/= 12, nursing home admission, and death. RESULTS: The possible AD classification has been simplified in six categories: possible AD with cerebrovascular disease (CVD) (69%), with history of alcohol abuse (15%), with history of depression (7%), with thyroid disease (4%), with history of head trauma (6%), with vitamin B12 deficiency (6%), and with other disease process that may have affected the clinical presentation of AD (4%). The presence of CVD, history of alcohol abuse, and history of depression concomitant with the onset of dementia were associated with time to death. Neither thyroid disease, history of head trauma, nor vitamin B12 deficiency were associated with any of the four endpoints. CONCLUSION: This cohort showed that comorbid conditions that can affect cognition delineate clearly defined subgroups in AD. The presence of environmental or other brain disorders sufficient to produce dementia appears to affect physical survival in patients with AD, but not functional and cognitive decline or institutionalization.

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PubMed2000

Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression.

The relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) to antidepressant response was examined in 95 elderly patients receiving a protocolized treatment for depression with paroxetine or nortriptyline. Patients were treated for up to 12 weeks and assessed weekly with clinical ratings and measurements of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were found to have the ll genotype and 30 had at least one s allele. There were no baseline differences between these groups in pretreatment Hamilton Rating Scale for Depression (HRSD) scores or anxiety symptoms. During acute treatment with paroxetine, mean reductions from baseline in HRSD were significantly more rapid for patients with the ll genotype than for those possessing an s allele, despite equivalent paroxetine concentrations. Onset of response to nortriptyline was not affected. Allelic variation of 5-HTTLPR may contribute to the variable initial response of patients treated with a selective serotonin reuptake inhibitor.

Adrenergic alpha-Agonists↗

PubMed2000

Psychotic symptoms in Alzheimer's disease are not associated with more severe neuropathologic features.

Psychotic symptoms in Alzheimer's disease (AD) have been associated with increased rates of cognitive impairment and functional decline. Prior studies have been conflicting with regard to whether AD patients with psychosis (AD+P) have evidence of more severe neuropathologic findings at postmortem exam. We examined the severity of neuritic plaques and neurofibrillary tangles in six brain regions--middle frontal cortex, hippocampus, inferior parietal cortex, superior temporal cortex, occipital cortex, and transentorhinal cortex-in 24 AD+P subjects and 25 matched AD subjects without psychosis (AD-P). All analyses controlled for the presence of cortical Lewy bodies, and corrected for multiple comparisons. We found no significant associations between neuritic plaque and neurofibrillary tangle severity and AD+P, and no significant associations with any individual psychotic symptom. The association of AD+P with a more rapidly progressive course of AD appears to be mediated by a neuropathologic process other than increased severity of plaque and tangle formation.

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PubMed2000

Pharmacologic profile of perphenazine's metabolites.

The authors have previously reported that in elderly patients treated with low doses of perphenazine, few extrapyramidal symptoms (EPS) developed in those who were not poor CYP2D6 metabolizers. The authors hypothesized that this atypical side effect profile is due to perphenazine's principal metabolite, n-dealkylperphenazine (DAPZ), which is usually present in vivo at concentrations 1.5 to 2 times that of the parent drug. Perphenazine, DAPZ, and 7-hydroxyperphenazine affinities were examined in vitro by competition-binding analysis to isolated human receptors expressed in transfected cell lines. Perphenazine and metabolite effects were examined in vivo in 54 older patients who were treated with perphenazine, at a target dose of 0.1 mg/kg, for 10 to 17 days. Drug concentrations were determined by high-performance liquid chromatography with electrochemical detection. In in vitro binding studies, DAPZ demonstrated a higher affinity for serotonin-2A receptors than for dopamine-2 receptors to an extent comparable to that of some atypical neuroleptic agents. In contrast, perphenazine and 7-hydroxyperphenazine demonstrated a higher affinity for dopamine-2 receptors than for serotonin-2A receptors. The mean +/- SD concentrations in the 54 subjects were the following: perphenazine, 1.5 +/- 1.4 ng/mL; DAPZ, 2.0 +/-1.6 ng/mL; and 7-hydroxyperphenazine, 0.8 +/- 1.9 ng/mL. The mean +/- SD quotient for the DAPZ/perphenazine concentration was 1.7 +/- 1.1 and for the 7-hydroxyperphenazine/perphenazine was 0.54 +/-1.6. EPS onset was not correlated with the perphenazine concentration, the metabolite concentrations, the DAPZ/perphenazine quotient, or the 7-hydroxyperphenazine/perphenazine quotient. Despite a moderately atypical receptor-binding profile, DAPZ does not seem to moderate perphenazine effects in vivo in older patients. This outcome likely reflects the low potency of DAPZ for dopamine-2 and serotonin-2A receptors relative to the potency of perphenazine for these receptors. Further exploration of atypical properties of DAPZ should include de novo administration of this metabolite in animal models.

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