Association of plasma homovanillic acid with behavioral symptoms in patients diagnosed with dementia: a preliminary report.

Neuroleptic treatment of psychotic symptoms or agitated behavior in elderly patients diagnosed with dementia is associated with reduced efficacy and increased rates of neuroleptic-induced parkinsonism in comparison to younger patients with schizophrenia. We report the first study to examine the relationship between an in vivo measure of dopaminergic function, plasma homovanillic acid (pHVA), and ratings of psychosis, agitation, and parkinsonism before and after neuroleptic treatment in dementia patients. Pretreatment pHVA was significantly correlated with parkinsonian rigidity, with a trend observed with agitation and hostility. Though mean pHVA did not change during perphenazine treatment, intraindividual change in pHVA at day 15 was correlated with improvement in hostility, with a similar trend for improvement in agitation. These preliminary findings are consistent with reports associating dopaminergic function with agitated, but not psychotic, symptoms in patients diagnosed with dementia, and with a reduced responsivity of dopaminergic systems to neuroleptic treatment in these patients.

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.

Prolactin response to neuroleptic challenge in late-life psychosis.

Psychosis in the elderly is superimposed on both age-related and disease-specific declines in dopaminergic function. Though the prolactin (PRL) response to neuroleptic challenge has been used as an in vivo measure of dopaminergic function in midlife adults, it remains uninvestigated in late-life psychoses. We examined the PRL response to intravenous perphenazine (PZ) in 11 elderly patients with psychotic symptoms complicating either a major depression (MD-P) or a dementia. The magnitude of increase in prolactin after PZ divided patients into three non-overlapping groups: dementia patients had a bimodal response and MD-P patients fell between the dementia groups. Our findings suggest that the PRL response to PZ may provide an in vivo measure of dopaminergic function in elderly patients. This finding must be confirmed through correlation with other measures of dopaminergic function in late-life psychoses and with measures of neuroleptic response and neuroleptic-induced extrapyramidal effects.

Serotonin 5-HT3 receptor binding kinetics in the cortex of suicide victims are normal.

Serotonergic abnormalities have been identified in the brain of suicide victims independent of psychiatric diagnosis. We report the first study of serotonin 5-HT3 receptors in the brain of suicide victims. There were no differences in the number (Bmax) or affinity (KD) of 5-HT3 receptors in the temporal cortex of suicide victims compared to matched controls. There was a negative correlation between brain serotonin levels and receptor number (r = -0.5, p = 0.04) in both groups. This study indicates that alterations in serotonergic function in the brain of suicide victims do not appear to directly involve the 5-HT3 receptor.

Lower 3H-paroxetine binding in cerebral cortex of suicide victims is partly due to fewer high affinity, non-transporter sites.

Suicide has been associated with decreased serotonin transmission. Measurement of concentrations of serotonin, its precursors tryptophan (TRY) and 5-hydroxytryptophan (5-HTP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), have been used as indices of serotonin activity, and with serotonin transporter binding, are indices of the integrity of serotonin nerve terminals. Most previous studies have not distinguished high affinity transporter binding from a very similar nontransporter binding site, where binding is not dependent on Na+ or Cl- and that does not have a known functional role. We therefore, assayed binding kinetics in prefrontal (PFC) and temporal cortex (TC) in matched pairs of suicide victims and controls using the selective ligand 3H-paroxetine, and employing 1 microM sertraline to define specific binding to the transporter and 10 microM sertraline which also displaces binding to the high affinity, nontransporter site. In addition, we measured concentrations of TRY, 5-HTP, serotonin and 5-HIAA in the same brain areas. The total number of 3H-paroxetine transporter and nontransporter binding sites (Bmax), was lower in the suicide group compared to controls in both Brodmann area 9 (prefrontal cortex; p = 0.02) and in Brodmann area 38 (temporal cortex, p = 0.01). In contrast, no differences were found in the number of high affinity transporter binding sites and concentrations of serotonin, 5-HIAA, 5-HTP or TRY (p > 0.05). We conclude that the number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer 3H-paroxetine and 3H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites.

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.

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.