Psychosis in Alzheimer Disease and Elevations in Disease-Relevant Biomarkers.

Importance: The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology. Objective: To investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD. Design, Setting, and Participants: This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023. Exposures: Plasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis. Main Outcomes and Measures: Plasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire. Results: The cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-ß positivity (Aß+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis. Conclusions and Relevance: Results of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.

ApoE elevation is associated with the persistence of psychotic experiences from age 12 to age 18: Evidence from the ALSPAC birth cohort.

Apolipoproteins, which play important roles in lipid metabolism, innate immunity and synaptic signalling, have been implicated in first episode psychosis and schizophrenia. This is the first study to investigate plasma apolipoprotein expression in children with psychotic experiences that persist into adulthood. Here, using semi-targeted proteomic analysis we compared plasma apolipoprotein expression levels in age 12 subjects who reported psychotic experiences at both age 12 and age 18 (n = 37) with age-matched subjects who only experienced psychotic experiences (PEs) at age 12 (n = 38). Participants were recruited from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. We identified apoE, a protein with significant regulatory activity on cholesterol metabolism in the brain, to be significantly up regulated (p < 0.003) in those with persistent psychotic experiences. We confirmed this finding in these samples using ELISA. Our findings indicate elevated plasma apoE in age 12 children who experience PEs is associated with persistence psychotic experiences.

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease.

OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹8F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe.

Ketamine produces effects in healthy humans that resemble the positive, negative and cognitive symptoms of schizophrenia. We investigated the effect of ketamine administration on brain activity as indexed by blood-oxygen-level-dependent (BOLD) signal change response, and its relationship to ketamine-induced subjective changes, including perceptual distortion. Thirteen healthy participants volunteered for the study. All underwent a 15-min functional MRI acquisition with a ketamine infusion commencing after 5 min (approx 0.26 mg/kg over 20s followed by an infusion of approx. 0.42 mg/kg/h). Following the scan, participants self-rated ketamine-induced effects using the Psychotomimetic States Inventory. Ketamine led to widespread cortical and subcortical increases in BOLD response (FWE-corrected p < 0.01). Self-rated perceptual distortions and delusional thoughts correlated with increased BOLD response in the paracentral lobule (FWE-corrected p < 0.01). The findings suggest that BOLD increases in parietal cortices reflect ketamine effects on circuits that contribute to its capacity to produce perceptual alterations and delusional interpretations.

[Pregabalin--a drug with abuse potential?]. / Pregabalin--ein Arzneistoff mit Missbrauchspotential?

A case of pregabalin misuse associated with delusional ideas in a drug addict is reported. Pregabalin has been approved as an adjunct therapy for epilepsy, but also for neuropathic pain and generalized anxiety disorders and is widely used today. It has also been used in clinical trials to study its potential utility as a treatment for tobacco, alcohol and benzodiazepine addiction. Web sites, case reports and an epidemiological study (Swedish National Register of Adverse Drug Reactions) suggest that the drug may be abused, especially by substance-dependent individuals. Pregabalin was analyzed by LC/MS/MS following precipitation of serum proteins. Vigabatrin was used as internal standard. The concentration of 25 pg pregabalin/mL serum determined in the present case is the second highest value published so far after misuse of the substance. Due to paradoxical agitation, anxiety attacks and abnormal thinking, the man was exculpated. Further studies are required to assess the actual abuse potential of pregabalin.

Identification of blood biomarkers for psychosis using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

[Risperidone intoxication in a patient with a genetic predisposition as "poor [non]metabolizer"]. / Risperidonintoxikation bei genetischer Disposition als "poor [non]metabolizer".

OBJECTIVE: The enzyme system cytochrome P450 plays a central role in the metabolism of drugs in the human body. The enzyme CYP2D6 is important for the metabolism of psychoactive agents. Genetic changes in the CYP2D6 gene can lead to reduced or absent activity. METHODS: We report on a 37-year-old female patient who was given risperidone to treat an acute delusional disorder. Despite receiving a very low dose, the patient suffered from an intoxication. We inferred that an excessively raised plasma level of risperidone may result from a pharmacologically relevant disorder of metabolism. RESULTS: The molecular genetic investigation revealed a compound heterozygous mutation in the CYP2D6 gene and thus documented a genetic predisposition as a "poor [non]metabolizer". CONCLUSIONS: In intoxications with psychoactive agents, the presence of an enzyme defect in the P450 system should be considered as an additional possible cause.

Delusion of pregnancy associated with antipsychotic induced metabolic syndrome.

Metabolic syndrome is currently the research topic of several studies. Although physical manifestations of metabolic syndrome have been described, the psychological and psychiatric impact of metabolic syndrome has not been studied to date. We report the first case of antipsychotic-induced metabolic syndrome which was associated with development of delusions of pregnancy in a post-menopausal woman.

[Therapeutic drug monitoring: A pharmacotherapeutic tool in psychiatry]. / Arzneimittelspiegel als pharmakotherapeutisches Werkzeug bei der Behandlung mit Psychopharmaka.

Therapeutic drug monitoring (TDM) is used increasingly for managing psychiatric outpatients, where the preanalytic error risk is high. Blood samples must be collected under steady-state conditions immediately before ingestion of the morning dose or before the next injection. In order to interpret the plasma levels accurately, age, gender, ethnicity, compliance, drug dosage, renal and hepatic function and comedication incl. smoking habits and diet (esp. caffeine intake and consumption of grapefruit juice) have to be taken into account. If in doubt, aberrant plasma levels should be confirmed by a second control under optimized conditions. Pharmacogenetic testing enables the identification of abnormal metabolizers. TDM and pharmacogenetic tests are useful tools to improve pharmacotherapy by preventing dose-dependent adverse drug events, optimizing dosage during long-term treatment and identifying ultrarapid metabolizers and malcompliance.

Platelet serotonin in combat related posttraumatic stress disorder with psychotic symptoms.

BACKGROUND: Combat-related posttraumatic stress disorder (PTSD) is severe form of PTSD, frequently associated with psychotic symptoms. Platelet serotonin (5-hydroxytryptamine, 5-HT) was used as a peripheral 5-HT marker to identify particular symptoms in PTSD. METHODS: Platelet 5-HT was determined fluorimetrically in 67 war veterans with combat related PTSD, 36 combat exposed veterans who did not develop PTSD, 35 veterans with PTSD complicated with psychotic features. PTSD diagnosis of current and chronic PTSD, and clinical symptoms of PTSD and psychoses were assessed according to DSM-IV criteria, using the Clinician Administrated PTSD Scale, and Positive and Negative Syndrome Scale (PANSS). RESULTS: Platelet 5-HT concentration was significantly higher in veterans with psychotic PTSD than in veterans with non-psychotic PTSD, veterans without PTSD, or in control subjects. Platelet 5-HT was significantly positively correlated with the positive symptoms in PANSS subscale, and with the symptoms of delusions within PANSS positive subscale. LIMITATIONS: The results were obtained on peripheral 5-HT marker, i.e. platelet 5-HT concentration. CONCLUSIONS: Since the delusions are the core psychotic symptoms occurring in our psychotic PTSD patients, the result of the increased platelet 5-HT concentration, associated with delusions, indicate that platelet 5-HT might be used as a trait marker of psychotic symptoms in PTSD, but not as a state marker for PTSD.

24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression.

BACKGROUND: Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients. METHODS: Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours. RESULTS: Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices. CONCLUSION: In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.

Platelet MAO-B activity and serotonin content in patients with dementia: effect of age, medication, and disease.

This study aimed at determining the effect of drug therapy, age and type of dementia on biological markers. Both platelet monoamine oxidase type B (MAO-B) activity and serotonin content of 57 demented patients and 20 control subjects were determined. Platelet MAO-B activity was measured using [14C]tyramine as substrate. Serotonin content was determined by HPLC-EC method. Increased platelet serotonin content and platelet count was found in patients with dementia compared to controls. A positive correlation was experienced between platelet MAO-B activity, platelet serotonin content and age. Platelet MAO-B activity was higher in the haloperidol treated group, compared with patients treated with anxyolitics. The main original finding of the present study is that platelet serotonin content is increased in demented patients with delusions compared to dementia without complications (p = 0.006). It seems, that platelet MAO-B activity is influenced mainly by drug therapy, while serotonin content rather reflects clinical characteristics in dementia.

Growth hormone response to growth hormone releasing hormone in non-delusional and delusional depression and healthy controls.

Growth hormone (GH) responses to growth hormone releasing hormone (GHRH) of 53 in-patients meeting DSM-III-R criteria for major depressive episode with melancholia (24 non-delusional and 23 delusional depression) were compared with those of 19 healthy controls. No significant differences in basal GH were found between the control and either the non-delusional or the delusional groups. The whole group of depressed patients showed a significantly lower response than the control patients at all points of the GH response to GHRH curve as well as a lower area under curve. When the three groups (control, delusional, and non-delusional depressed) were compared, it was found that only the non-delusional depressed patients had a significantly lower area under curve and lower values at +60, +90 and +120 min than the controls. The only significant difference between the two groups of depressed patients was that the delusional group showed a delayed appearance of the maximum response peak and a more prolonged response.

Dopamine uptake by platelets from subjects with schizophrenia: a correlation with the delusional state of the patient.

The uptake of 3H-dopamine by platelets from patients with a number of psychiatric disorders has been compared with that by platelets from normal volunteers. Overall, 3H-dopamine uptake by platelet-rich plasma (PRP) from 25 schizophrenic subjects did not differ from 3H-dopamine uptake by PRP from 22 nonschizophrenic patients and 61 normal volunteers. In the schizophrenic group, however, there was an increased spread of results with seven values falling outside the range of results observed in the control group. Furthermore, of the patients rated, only for the schizophrenic patients was there an inverse correlation between 3H-dopamine uptake by platelets and the rating for delusions on the Scale for the Assessment of Positive Symptoms. Thus, 3H-dopamine uptake by platelet seems, in some way, to be linked to be delusional state of the patient. Further study of 3H-dopamine uptake by platelets is warranted in a larger and more diverse group of patients to determine the significance of altered dopamine uptake by platelets from some schizophrenic subjects and the correlation between platelet 3H-dopamine uptake and the delusional state of these subjects.

Measurement of haloperidol reductase activity in red blood cells and reduced haloperidol/haloperidol ratios in plasma in oriental psychiatric patients.

1. The authors established a method for measuring haloperidol (HAL) reductase activity in human red blood cells. 2. Characteristics of the HAL reductase in red blood cells were examined. This enzyme reaction was NADPH dependent, and the optimum pH was at 8.2-8.9. Vmax and Km were calculated as 25-150 pmol/hr/10(6) RBC and 160-2600 microM respectively. 3. HAL reductase activities in red blood cells from 14 patients treated with HAL were in a range of 9.7-20.8 pmol/hr/10(6) RBC. So far we did not find any significant correlation between HAL reductase activities and reduced HAL/HAL ratios in plasma.

Plasma postdexamethasone cortisol levels in schizoaffective disorder.

The degree of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in depressed patients with schizoaffective disorder was compared to that seen in patients with major depressive disorder with and without delusional features. The frequency of nonsuppression to dexamethasone was similar for all three diagnostic groups. Maximum postdexamethasone plasma cortisol was greater for delusional depressives, but did not differ between patients with major depressive and schizoaffective disorders. Modest correlations were found between postdexamethasone plasma cortisol levels, severity of illness, age, and recent weight loss, for patients with both major depressive disorder and delusional depression. For schizoaffective patients, associations between postdexamethasone plasma cortisol levels and various measures of severity of illness, but not age and recent weight loss, were found. Although HPA axis dysregulation occurs more frequently in all three of the studied diagnostic groups than in normal individuals, factors contributing to this dysregulation may be qualitatively different for schizoaffective patients.