An ecological study of objective rest-activity markers of lithium response in bipolar-I-disorder.

BACKGROUND: Despite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest-activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR). METHODS: Seventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR). RESULTS: Twenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06). CONCLUSIONS: To our knowledge, this is the largest actigraphy study of rest-activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups.

Chronotypes and circadian rest-activity rhythms in bipolar disorders: a meta-analysis of self- and observer rating scales.

OBJECTIVE: Chronobiological models postulate that abnormalities in circadian rest/activity rhythms (CRAR) are core phenomena of bipolar disorders (BDs). We undertook a meta-analysis of published studies to determine whether self- or observer ratings of CRAR differentiate BD cases from comparators (typically healthy controls [HCs]). METHOD: We undertook systematic searches of four databases to identify studies for inclusion in random effects meta-analyses and meta-regression analyses. Effect sizes (ES) for pooled analyses of self- and observer ratings were expressed as standardized mean differences with 95% confidence intervals (CIs). RESULTS: The 30 studies meeting eligibility criteria included 2840 cases and 3573 controls. Compared with HC, BD cases showed greater eveningness (ES: 0.33; 95% CI: 0.12-0.54), lower flexibility of rhythms (ES: 0.36; 95% CI: 0.06-0.67), lower amplitude of rhythms (ES: 0.55; 95% CI: 0.39-0.70) and more disturbances across a range of CRAR (ES of 0.78-1.12 for general and social activities, sleep and eating patterns). Between study heterogeneity was high (I2  > 70%) and evidence indicated a potential publication bias for studies using the Biological Rhythms Interview of Assessment in Neuropsychiatry. Meta-regression analyses suggested significantly larger ES were observed in studies using observer ratings or including BD cases with higher levels of depressive symptoms. CONCLUSION: This meta-analysis demonstrates that BD is associated with higher levels of self- or observer-rated CRAR disturbances compared with controls. However, further studies should examine the respective performance of individual instruments when used alone or in combination, to clarify their applicability and utility in clinical practice.

Do self-ratings of the Pittsburgh Sleep Quality Index reflect actigraphy recordings of sleep quality or variability? An exploratory study of bipolar disorders versus healthy controls.

Sleep disturbances are typical symptoms of acute episodes of bipolar disorder (BD) and differentiate euthymic BD cases from healthy controls (HC). Researchers often employ objective recordings to evaluate sleep patterns, such as actigraphy, whilst clinicians often use subjective ratings, such as the Pittsburgh Sleep Quality Index (PSQI). As evidence suggests the measures may disagree, we decided to compare subjective (PSQI) and objective (3 weeks of actigraphy) sleep profiles in BD cases and HC (n = 154). We examined whether a dimensional approach helps to illustrate different patterns of sleep disturbances and whether the concordance between subjective and objective recordings varies according to clinical status (BD versus HC). Principal component analysis (PCA) extracted two factors from the PSQI, and separate PCAs of actigraphy recordings extracted two factors for mean values of sleep parameters and one factor for intra-individual variability. Correlational and linear regression analyses of PCA-derived dimensions demonstrated that, in both BD and HC, a PSQI "Sleep duration-efficiency" factor was significantly correlated with an actigraphy "Sleep initiation-duration" factor. Furthermore, in BD cases only, the PSQI total score and a PSQI "Sleep Impairments" factor were each significantly correlated with an actigraphy "Sleep Variability" factor. Overall, we found that subjective experiences of sleep may be modulated by different components of objectively recorded sleep in BD compared with HC. Also, the use of PCA enabled us to consider the multi-dimensional nature of subjective sleep, whilst the inclusion of intra-individual sleep variability afforded a more subtle evaluation of objective sleep.

Gene expression of circadian genes and CIART in bipolar disorder: A preliminary case-control study.

Based on the observed circadian rhythms disruptions and sleep abnormalities in bipolar disorders (BD), a chronobiological model has been proposed suggesting that core clock genes play a central role in the vulnerability to the disorder. In this context, the analysis of circadian genes expression levels is particularly relevant, however studies focused on the whole set of core clock genes are scarce. We compared the levels of expression of 19 circadian genes (including the recently described circadian repressor (CIART)) in 37 euthymic individuals with BD and 20 healthy controls (HC), using data obtained by RNA sequencing of lymphoblastoid cell lines and validated the results using RT-qPCR. RNA sequencing data showed that CIART gene expression was correlated with those of ARNTL, ARNTL2, DBP, PER2 and TIMELESS. Data from RNA sequencing showed that the level of expression of four circadian genes (ARNTL, ARNTL2, BHLHE41 and CIART) discriminated individuals with BD from HC. We replicated this result using RT-qPCR for ARNTL and CIART. This study suggests that an imbalance between activation/repression of the transcription within the circadian system in individuals with BD as compared to HC and as such opens avenues for further research in larger independent samples combining both expression and epigenetic analyses.

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.

Can actigraphy be used to define lithium response dimensions in bipolar disorders?

BACKGROUND: Actigraphy is commonly used in case-control studies to explore sleep-wake patterns and circadian rhythmicity in bipolar disorders (BD). However, there is limited ecological research regarding actigraphy parameters associated with response to lithium (Li_Resp). METHODS: Outpatients with BD-I (n=70) and BD-II (n=20) who were all prescribed prophylactic Li undertook 21 consecutive days of actigraphy recording. The Retrospective Assessment of Response to Lithium Scale (also referred as the Alda scale) was rated on a 0-10 continuum. We used principal component analysis (PCA) to summarize interrelationships among clinical and actigraphic variables and Li_Resp. RESULTS: PCA demonstrated the existence of a Li_Resp dimension (accounting for >20% explained variance) characterized by 5 markers of circadian timing and rhythmicity. Replication of the PCA, using the resampling procedure, confirmed this model was robust for the BD-I but not for BD-II (which showed weaker associations between Li_Resp and sleep variables). These circadian rhythm markers identified by PCA correctly classified 64% (95% Confidence Intervals: 52-76%; p<0.03) of all BD cases as Li responders or non-responders. LIMITATIONS: Although we attempted to minimize risk of statistical error, the small BD-II subsample may have undermined the ability of PCA to identify a robust Li_Resp dimension for this subtype. CONCLUSIONS: Our findings are compatible with circadian models of BD and with putative mechanisms of action of Li. If confirmed in prospective studies, the study offers support for use of actigraphy as a relevant method for real time objective monitoring of Li_Resp, with few concerns regarding reliability and validity.

Occurrence of Side Effects in Treatment-Resistant Depression: Role of Clinical, Socio-Demographic and Environmental Characteristics.

Introduction: Treatment-resistant depression (TRD) is a disabling psychiatric condition characterized by the failure of two antidepressants (ADs). Since the occurrence of side effects (SEs) appears to be one of the main determinants of early discontinuation of pharmacological treatments contributing to a pseudo-resistance, the purpose of this study was to determine the parameters associated with the occurrence of SEs under ADs in a cohort of patients with TRD. Methods: An observational, cross-sectional, multicentre study was carried out using data from the French network of Expert Centers for TRD. For the 108 patients enrolled in the study, the statistical analyses focused on the overall occurrence and on the profile of the SEs (9 categories, 32 items). Results: SEs were influenced by age and sex and were positively associated with the intensity of anxious, depressive and suicidal symptoms, a history of childhood trauma (sexual abuse, emotional abuse and neglect), and negatively associated with self-esteem, and assessment of overall functioning. Conclusion: Using variables accessible in common practice, these results fall within the dynamic of a more tailored approach to medicine that could allow, through integrated pharmacological management, the continuation of antidepressant treatments, and therefore limit the risk of therapeutic failure.

Alterations in circadian rhythms following alcohol use: A systematic review.

Increasing evidence suggest a bidirectional link between disrupted circadian rhythms and alcohol use disorders (AUD). A better understanding of these alcohol-induced changes in circadian rhythms will likely provide important therapeutic solutions. We conducted a systematic review based on the PubMed database examining biological rhythms in all stages of alcohol use: acute alcohol consumption, AUD, alcohol withdrawal, and abstinence. Different changes in circadian rhythms have been observed after a single acute alcohol intake, but also during AUD and alcohol withdrawal. Following a single acute alcohol intake, changes in biological rhythms are dose-dependent, reflected in the melatonin and cortisol secretions, and the core body temperature (CBT) rhythms. These alterations normalize the next morning and appear mostly for acute alcohol intake higher than 0.5 g/kg. These alterations are more severe during AUD and persist over time. In addition, interestingly, opposite patterns of the melatonin physiological ratio between diurnal and nocturnal secretion (N/D ratio < 1) have been observed during AUD and appear to be a marker of chronic daily use. During alcohol withdrawal, circadian rhythms desynchronization correlates with the severity of alcohol withdrawal symptoms and withdrawal complications such as delirium tremens. During abstinence a resynchronization of circadian rhythms of cortisol and CBT appears in most patients about 1 month after alcohol withdrawal. Disruption of melatonin circadian rhythms can persist after 3-12 weeks of abstinence. The circadian genetic vulnerability associated with biological rhythms alterations in alcohol use disorders increases the risk of relapses. Circadian-based interventions could play a critical role in preventing and treating AUD.

Can olfactory dysfunction be a marker of trait or states of bipolar disorders? A comprehensive review.

BACKGROUND: Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in which phase of the disease, to know if they could be a marker of state or trait. METHODS: A Systematic Literature Review was conducted using PRISMA guidelines to include all studies assessing olfaction with objective measures in BD. RESULTS: 9 studies were identified. All of them have assessed odour identification and 3 reported deficits mainly in patients with psychotic features or elements of illness severity in comparison to healthy subjects. There is no difference in threshold of perception between BD patients and controls and it is no possible to conclude for discrimination because only one study has assessed this dimension in comparison to control. We cannot conclude for hedonic value of odours regarding these studies. LIMITATIONS: These studies are very incomplete because only one has evaluated all the processes involved in olfaction process. CONCLUSIONS: In light of this review, evidence is still missing to unveil potential disturbances of olfactory process as a marker of BD. These new avenues of research could help to clarify the links between OD and BD and provide information on the pathophysiology of the disorder according to the impaired dimension.

Misperception of sleep in bipolar disorder: an exploratory study using questionnaire versus actigraphy.

BACKGROUND: The concept of misperception of sleep refers to the estimated discrepancy between subjective and objective measures of sleep. This has been assessed only in a few prior studies in individuals with Bipolar Disorder (BD) as compared to Healthy Controls (HC) and with mixed results. METHODS: We assessed a sample of 133 euthymic individuals with BD and 63 HC for retrospective subjective (Pittsburgh Sleep Quality Index) and objective (21 days of actigraphy recording) measures of total sleep time, sleep latency and sleep efficiency. We first investigated the correlations between these subjective and objective measures in the two groups. We then compared individuals with BD and HC for the absolute values of the differences between subjective and objective sleep parameters, used as a proxy of the magnitude of misperception of sleep. Finally, we undertook regression analyses to assess associations between clinical groups, core demographics, clinical factors and misperception of sleep. RESULTS: The correlation coefficients between subjective and objective measures of sleep did not differ between groups (total sleep time: rho = .539 in BD and rho = .584 in HC; sleep latency: rho = .190 in BD and rho = .125 in HC; sleep efficiency: rho = .166 in BD and rho = .222 in HC). Individuals with BD did not differ from HC in the magnitude of misperception of total sleep time, sleep latency nor sleep efficiency. Individuals with BD type 1 misperceived their sleep efficiency significantly more than individuals with BD type 2, with no further difference between BD type 1 and BD type 2 regarding sleep latency and sleep duration misperceptions. Three factors (age, symptoms of obstructive sleep apnea, and mild depressive symptoms), were the main contributors to the magnitude of misperception of sleep. CONCLUSIONS: Misperception of sleep was not associated with a diagnosis of BD. In this sample, mild depressive symptoms, older age, or symptoms of obstructive sleep apnea may be related to greater sleep misperception. In that case, the reliability of subjective measures may decrease as the misperception of sleep increases. This study may help guide clinicians in selecting the best approach for assessing sleep (objective versus subjective measures) in individuals with BD.

Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla.

BACKGROUND: Lithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used 7Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years. METHODS: Three-dimensional 7Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T1 and T2 relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel- and parcellation-based group analyses were conducted for the first time for 7Li magnetic resonance imaging. RESULTS: Using unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li]B ≈ 0.40 × [Li]P, R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort. CONCLUSIONS: This observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD.

Eveningness and poor sleep quality contribute to depressive residual symptoms and behavioral inhibition in patients with bipolar disorder.

Eveningness and sleep disturbances are considered as markers of Bipolar Disorder (BD) and influence mood and emotional or behavioral states. This study investigates the associations between circadian markers and sleep quality on residual depressive symptoms and inhibition/activation dimensions during the euthymic phase. A sample of 89 euthymic adult individuals with BD was assessed for circadian preference and typology using the Composite Scale of Morningness (CSM) and the Circadian Type Inventory (CTI) and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). The Montgomery and Asberg Depression Rating Scale (MADRS) and the Multidimensional Assessment of Thymic States (MAThyS) were used to measure residual depressive symptoms and the inhibition/activation dimensions. We examined any associations between these parameters using correlations and path analyses. We identified significant associations between eveningness and poorer sleep quality that correlated to higher depressive residual symptoms and a global inhibition. The use of path analyses led us to conclude that poor sleep quality mediated the relationship between eveningness and either residual mood symptoms or behavioral inhibition (motivation, sensory perception, interpersonal interaction, and cognition). These factors should be considered in the clinical evaluation of individuals with BD, with a specific attention during the euthymic phase, in order to achieve the best functional outcome possible.