Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review.

Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Cytochromes P450 and P-Glycoprotein Phenotypic Assessment to Optimize Psychotropic Pharmacotherapy: A Retrospective Analysis of Four Years of Practice in Psychiatry.

Altered cytochromes P450 enzymes (CYP) and P-glycoprotein transporter (P-gp) activity may explain variabilities in drug response. In this study, we analyzed four years of phenotypic assessments of CYP/P-gp activities to optimize pharmacotherapy in psychiatry. A low-dose probe cocktail was administered to evaluate CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4, and P-gp activities using the probe/metabolite concentration ratio in blood or the AUC. A therapeutic adjustment was suggested depending on the phenotyping results. From January 2017 to June 2021, we performed 32 phenotypings, 10 for adverse drug reaction, 6 for non-response, and 16 for both reasons. Depending on the CYP/P-gp evaluated, only 23% to 56% of patients had normal activity. Activity was decreased in up to 57% and increased in up to 60% of cases, depending on the CYP/P-gp evaluated. In 11/32 cases (34%), the therapeutic problem was attributable to the patient's metabolic profile. In 10/32 cases (31%), phenotyping excluded the metabolic profile as the cause of the therapeutic problem. For all ten individuals for which we had follow-up information, phenotyping allowed us to clearly state or clearly exclude the metabolic profile as a possible cause of therapeutic failure. Among them, seven showed a clinical improvement after dosage adaptation, or drug or pharmacological class switching. Our study confirmed the interest of CYP and P-gp phenotyping for therapeutic optimization in psychiatry.

Chronic Lithium Therapy and Urine-Concentrating Ability in Individuals With Bipolar Disorder: Association Between Daily Dose and Resistance to Vasopressin and Polyuria.

Introduction: Lithium treatment can induce nephrogenic diabetes insipidus (NDI), but no consensus intervention is offered to date. We evaluated in these patients patterns of urine concentration and the correlates of 24-hour urine output. Methods: Prospective, single-center, observational study of 217 consecutive lithium-treated individuals, with 24-hour urine collection, desmopressin (1-deamino-arginine vasopressin [DDAVP]) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in n = 119), and measured glomerular filtration rate (mGFR). Maximal urine osmolality (MaxUosm) was the highest level during the DDAVP test. Results: Of the individuals, 21% displayed polyuria (>3 l/d), but 55% displayed elevated fasting vasopressin level (>5 pg/ml). Uosm was significantly lower and urinary output and free water clearance were significantly higher in individuals treated for >10 years. MaxUosm was >600 mOsm/KgH2O in 128 patients (59%), among which vasopressin was increased in 51%, associated with higher lithium dose (950 [750-1200] vs. 800 [500-1000] mg/d, P < 0.001). All patients with lithium daily dose ≥1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose (ß 0.49 ± 0.17, P = 0.005), female sex (ß -359 ± 123, P = 0.004), daily osmolar intake (ß 2.21 ± 0.24, P < 0.001), MaxUosm (ß -2.89 ± 0.35, P < 0.001), and plasma vasopressin level (ß 10.17 ± 4.76, P = 0.03). Conclusion: Higher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce polyuria in these patients.

MRI-based kidney radiomic analysis during chronic lithium treatment.

BACKGROUND: Lithium therapy during bipolar disorder is associated with an increased risk of chronic kidney disease (CKD) that is slowly progressive and undetectable at early stages. We aimed at identifying kidney image texture features as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomics of T2-weighted magnetic resonance imaging (MRI). METHODS: One hundred and eight patients treated with lithium were evaluated including mGFR and kidney MRI, with T2-weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect an mGFR <60 ml/min/1.73 m². The texture index was validated using a training and a validation cohort. RESULTS: Texture analysis index was able to detect an mGFR decrease, with an AUC of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] vs. 46 [34-54] years, p = .001), with longer treatment duration (10 [3-22] vs. 6 [2-10] years, p = .02) and a lower mGFR (66 [46-84] vs. 83 [71-94] ml/min/1.73m², p < .001). Texture analysis index was independently and negatively associated with age (ß = -.004 ± 0.001, p < .001), serum vasopressin (-0.005 ± 0.002, p = .02) and lithium treatment duration (-0.01 ± 0.003, p = .001), with a significant interaction between lithium treatment duration and mGFR (p = .02). CONCLUSIONS: A renal texture index was developed among patients treated with lithium associated with a decreased mGFR. This index might be relevant in the diagnosis of lithium-induced renal toxicity.

Violent suicide attempt history in elderly patients with bipolar disorder: The role of sex, abdominal obesity, and verbal memory: Results from the FACE-BD cohort (FondaMental Advanced center of Expertise for Bipolar Disorders).

BACKGROUND: Bipolar disorder (BD) is a chronic, lifelong condition, associated with increased risk of obesity, cognitive impairment, and suicidal behaviors. Abdominal obesity and a higher risk of violent suicide attempt (SA) seem to be shared correlates with older age, BD, and male sex until middle age when menopause-related female body changes occur. This study aimed at assessing the role of abdominal obesity and cognition in the violent SA burden of individuals with BD. METHODS: From the well-defined nationwide cohort FACE-BD (FondaMental Advanced center of Expertise for Bipolar Disorders), we extracted data on 619 euthymic BD patients that were 50 years or older at inclusion. Cross-sectional clinical, cognitive, and metabolic assessments were performed. SA history was based on self-report. RESULTS: Violent SA, in contrast to non-violent and no SA, was associated with higher waist circumference, abdominal obesity and poorer California Verbal Learning Test short-delay free recall (CVLT-SDFR) (ANOVA, p < .001, p = .014, and p = .006). Waist circumference and abdominal obesity were associated with violent SA history independently of sex, BD type and anxiety disorder (Exp(B) 1.02, CI 1.00-1.05, p = .018; Exp(B) 2.16, CI 1.00-4.64, p = .009, accordingly). In an exploratory model, waist circumference and CVLT-SDFR performance mediated the association between male sex and violent SA. LIMITATIONS: Cross-sectional design and retrospective reporting. CONCLUSIONS: Violent SA history was associated with abdominal obesity and poorer verbal memory in older age BD patients. These factors were interlinked and might mediate the association between male sex and violent SA.

Characteristics of Bipolar Patients with Cognitive Impairment of Suspected Neurodegenerative Origin: A Multicenter Cohort.

Bipolar disorder is associated with an increased risk of dementia with aging. Little is known regarding this association, limiting appropriate diagnosis and management. We aimed to describe the characteristics of bipolar patients with late cognitive impairment for whom the hypothesis of an underlying neurodegenerative disease had been raised. We performed a retrospective multicenter study, recruiting bipolar patients over 50 years old from five French tertiary memory centers who had undergone cerebrospinal fluid (CSF) biomarker assessment for Alzheimer's disease (AD). Clinical, neuropsychological, and paraclinical characteristics were analyzed and 78 patients were included. The mean age at the onset of cognitive impairment was 62.4 years (±9.2). The mean MMSE score was 22.8 (±4.5), the mean FAB was 11.7 (±3.9), and the mean FCRST was 15.8 (±7.4)/36.8 (±9.7) (free/total recall). A total of 48.6% of the patients displayed cognitive fluctuations, and 38.2% showed cognitive improvement during follow-ups; and 56.3% of the patients showed Parkinsonism, of which 12.7% had never received antipsychotics. Among patients who underwent DAT-scans, 35.3% displayed dopaminergic denervation; 10.3% of patients had CSF AD biological signature ("A+ T+" profile), while 56.4% had other abnormal CSF profiles. Thus, clinical presentation was dominated by executive dysfunction, episodic memory impairment, fluctuating cognition, and a high frequency of Parkinsonism. Specifically, high frequency of delusional episodes suggests limited tolerance of psychotropic drugs. Most patients had abnormal CSF biomarker profiles, but only a minority displayed AD's specific biomarker signature. Therefore, while our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies rather than a common degenerative mechanism in the pathophysiology of this condition.

Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder.

Objectives: Early kidney damage during lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection. Methods: In this cross-sectional cohort study, 217 consecutive lithium-treated patients underwent mGFR and kidney MRI with half-Fourier turbo spin-echo and Single-shot with long echo time sequences. Results: Median age was 51 [27-62] years, and median lithium treatment duration was 5 [2-14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration (ß -0.8 [-1; -0.6] ml/min/1.73 m2 GFR decrease for each year of treatment), a higher age (ß -0.4 [-0.6; -0.3] ml/min/1.73 m2 for each year of age, p < 0.001), albuminuria (ß -3.97 [-6.6; -1.3], p = 0.003), hypertension (ß -6.85 [-12.6; -1.1], p = 0.02) and hypothyroidism (ß -7.1 [-11.7; -2.5], p = 0.003). Serum lithium concentration was not associated with mGFR. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as 1 year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r = -0.64, p < 0.001), but not in patients with no microcysts (r = -0.24, p = 0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73 m2 (AUC 0.893, p < 0.001, sensitivity 80%, specificity 81% for a cut-off value of five microcysts). Conclusion: Lithium treatment duration and hypothyroidism strongly impacted mGFR independently of age, especially in patients with microcysts. MRI might help detect early lithium-induced kidney damage and inform preventive strategies.

[Cognitive aging of bipolar patients]. / Le vieillissement cognitif des patients bipolaires.

Bipolar disorder is a severe, recurrent mood disorder, associated with a higher rate of morbidity and mortality. A new population of aging bipolar patients is emerging for which specific studies are scarce. There seem to be an association between bipolar disorder and major cognitive disorder, significantly affecting patients' psychosocial outcomes. Though the neuropathological mecanisms underlying such an evolution have yet to be found, there are three paradigms that can help us understand the clinical heterogeneity within the aging bipolar group. First, there seem to be different cognitive endophenotypes within the bipolar spectrum, related to different neurodevelopmental abnormalities. Each of these endophenotypes will interact with the normal cognitive aging process which is associated with a decline in certain cognitive domains while others remain stable. Nevertheless this cognitive decline will be variable from one patient to another. This can be explained by cognitive reserve which reflects the brain's capacity to endure neuropathology, and minimize clinical manifestations. The second hypothesis is the neuroprogression paradigm that offers an explanation on how a cyclic disorder such as bipolar disorder could evolve progressively into a major cognitive disorder. According to this paradigm, each manic and depressive episode is associated to an allostatic load, a systemic response associated with the secretion of neuroinflammatory factors which will secondarily alter the brain's connectivity. The third paradigm suggests that bipolar patients may develop either vascular dementia which is coherent with their increased vascular risk factor or another neurodegenerative disease. All three paradigms are not exclusive, and many other factors are to be taken into account such as medication, sensory impairment, health related changes and residual mood symptoms, which can alter cognitive functions.

White matter alterations in bipolar disorder: potential for drug discovery and development.

OBJECTIVES: Brain white matter (WM) alterations have recently emerged as potentially relevant in bipolar disorder. New techniques such as diffusion tensor imaging allow precise exploration of these WM microstructural alterations in bipolar disorder. Our objective was to critically review WM alterations in bipolar disorder, using neuroimaging and neuropathological studies, in the context of neural models and the potential for drug discovery and development. METHODS: We conducted a systematic PubMed and Google Scholar search of the WM and bipolar disorder literature up to and including January 2013. RESULTS: Findings relating to WM alterations are consistent in neuroimaging and neuropathology studies of bipolar disorder, especially in regions involved in emotional processing such as the anterior frontal lobe, corpus callosum, cingulate cortex, and in fronto-limbic connections. Some of the structural alterations are related to genetic risk factors for bipolar disorder and may underlie the dysfunctional emotional processing described in recent neurobiological models of bipolar disorder. Medication effects in bipolar disorder, from lithium and other mood stabilizers, might impact myelinating processes, particularly by inhibition of glycogen synthase kinase-3 beta. CONCLUSIONS: Pathways leading to WM alterations in bipolar disorder represent potential targets for the development and discovery of new drugs. Myelin damage in bipolar disorder suggests that the effects of existing pro-myelinating drugs should also be evaluated to improve our understanding and treatment of this disease.