Longitudinal assessment of ventricular volume trajectories in early-stage schizophrenia: evidence of both enlargement and shrinkage.

BACKGROUND: Lateral ventricular enlargement represents a canonical morphometric finding in chronic patients with schizophrenia; however, longitudinal studies elucidating complex dynamic trajectories of ventricular volume change during critical early disease stages are sparse. METHODS: We measured lateral ventricular volumes in 113 first-episode schizophrenia patients (FES) at baseline visit (11.7 months after illness onset, SD = 12.3) and 128 age- and sex-matched healthy controls (HC) using 3T MRI. MRI was then repeated in both FES and HC one year later. RESULTS: Compared to controls, ventricular enlargement was identified in 18.6% of patients with FES (14.1% annual ventricular volume (VV) increase; 95%CI: 5.4; 33.1). The ventricular expansion correlated with the severity of PANSS-negative symptoms at one-year follow-up (p = 0.0078). Nevertheless, 16.8% of FES showed an opposite pattern of statistically significant ventricular shrinkage during ≈ one-year follow-up (-9.5% annual VV decrease; 95%CI: -23.7; -2.4). There were no differences in sex, illness duration, age of onset, duration of untreated psychosis, body mass index, the incidence of Schneiderian symptoms, or cumulative antipsychotic dose among the patient groups exhibiting ventricular enlargement, shrinkage, or no change in VV. CONCLUSION: Both enlargement and ventricular shrinkage are equally present in the early stages of schizophrenia. The newly discovered early reduction of VV in a subgroup of patients emphasizes the need for further research to understand its mechanisms.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Season of the year, vitamin D and COVID-19.

Vitamin D supplementation reduced the risk of acute respiratory tract infection in two meta-analyses. Mendelian randomization shows a causal effect of low vitamin D on bacterial pneumonias risk. These studies involved patients before COVID-19 pandemic. Several association studies found higher incidence of SARS-CoV-2 positivity, greater COVID-19 severity and higher risk of mortality in vitamin D deficient subjects compared to vitamin D non-deficient controls. We draw attention to the trend of inverse relative COVID-19 mortality in Europe versus the states of the Southern Hemisphere (Australia, Brazil, South Africa) in dependence on season, which may be associated with intensity of ultraviolet radiation and consequent seasonal fluctuation of serum vitamin D levels. Although we cannot yet confirm causal role of vitamin D in SARS-CoV-2 positivity or COVID-19, we recommend consumption of vitamin D rich food or vitamin D supplementation in the non-sunny season to prevent vitamin D deficiency.

Beck Depression Inventory-II: Self-report or interview-based administrations show different results in older persons.

ABSTRACTBeck Depression Inventory-II (BDI-II) is one of the most-used rating scales. It was developed as a tool administered either as a self-rating or interview-based, observer-rating scale. OBJECTIVE: The goal of this study is to compare BDI-II scores obtained with two standard methods of administration in community-based older persons. METHODS: BDI-II was administered at first in the self-rated version to a sample of 60 mentally healthy older persons (age 60-87 years). Afterward, the interview-based administration was performed. ANALYSES: We compared the scores with nonparametric tests - Spearman's correlation coefficient and Wilcoxon Signed Ranks test. We also computed internal consistency. RESULTS: Self-rated BDI-II yielded significantly higher total score than interview (p < 0.001, P = 88%). The correlation between total scores was moderate (rs = 0.46, p < 0.001). Item analysis revealed a larger decrease (lower scores) in the somatic items in the interview-based version. CONCLUSIONS: The two methods of administration result in different total score in healthy older persons. Therefore, interpretation of the scores should reflect the administration, which should be always specified in the studies.

Montreal Cognitive Assessment and Mini-Mental State Examination reliable change indices in healthy older adults.

OBJECTIVE: Cognitive tests are used repeatedly to assess the treatment response or progression of cognitive disorders. The Montreal Cognitive Assessment (MoCA) is a valid screening test for mild cognitive impairment. The aim of our study was to establish 90% reliable change indices (RCI) for the MoCA together with the Mini-Mental State Examination (MMSE) in cognitively healthy older adults. METHOD: We analyzed 197 cognitively healthy and functional independent volunteers aged 60-94 years, who met strict inclusion criteria for four consecutive years. The RCI methods by Chelune and Hsu were used. RESULTS: For 1, 2, and 3 years, the 90% RCI for MoCA using Chelune's formula were -4 ≤, ≥4; -4 ≤, ≥4 and -5 ≤, ≥4 points, respectively, and -3 ≤, ≥3 for the MMSE each year. Ninety percent RCI for MoCA using Hsu's formula ranged from -6 to 0, respectively, and +3 to +8 dependent on the baseline MoCA. CONCLUSION: Our study demonstrated RCI for the MoCA and MMSE in a 3-year time period that can be used for the estimation of cognitive decline or improvement in clinical settings. Copyright © 2016 John Wiley & Sons, Ltd.

The Comparison of Effectiveness of Various Potential Predictors of Response to Treatment With SSRIs in Patients With Depressive Disorder.

The substantial non-response rate in depressive patients indicates a continuing need to identify predictors of treatment outcome. The aim of this 6-week, open-label study was (1) to compare the efficacy of a priori defined predictors: ≥20% reduction in MADRS score at week 1, ≥20% reduction in MADRS score at week 2 (RM ≥ 20% W2), decrease of cordance (RC), and increase of serum and plasma level of brain-derived neurotrophic factor at week 1; and (2) to assess whether their combination yields higher efficacy in the prediction of response to selective serotonin re-uptake inhibitors (SSRIs) than when used singly. Twenty-one patients (55%) achieved a response to SSRIs. The RM ≥20% W2 (areas under curve-AUC = 0.83) showed better predictive efficacy compared to all other predictors with the exception of RC. The identified combined model (RM ≥ 20% W2 + RC), which predicted response with an 84% accuracy (AUC = 0.92), may be a useful tool in the prediction of response to SSRIs.

How long does the pharmacokinetic interaction between carbamazepine and quetiapine last after carbamazepine withdrawal?

OBJECTIVES: Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS: In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. RESULTS: No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. CONCLUSION: We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.

Toward the processing speed theory of activities of daily living in healthy aging: normative data of the Functional Activities Questionnaire.

BACKGROUND: The aim of this study was to describe an instrumental activities of daily living (IADL) measure: Functional Activities Questionnaire (FAQ), which is often used in clinical settings as a self- or informant-based measure of IADL. However, the FAQ's relationship with age or education in healthy aging has not been investigated. METHODS: FAQ and a neuropsychological battery were administered to old and very old Czech adults (n = 540). Participants met strict inclusion criteria for the absence of any active or past neurodegenerative disorders. RESULTS: FAQ is significantly dependent on age and education, but not gender. Younger subjects and those with higher education have the lowest scores in the FAQ and show a higher degree of functional independence. FAQ moderately correlates with speed of processing, visual-perceptual and executive functions measures (Trail Making Tests, Stroop Test) and depressive symptoms, but not with episodic memory (WMS-III logical memory). We present normative percentile values for different age groups from 60 to 96 years of age. CONCLUSIONS: The present study shows conclusively that IADL measures, such as FAQ, should not be used without appropriate normative data, especially in very old adults. Thus, it has the ability to differentiate functional dependence due to age-related decline from neurodegenerative disease.

Using structural MRI to identify individuals at genetic risk for bipolar disorders: a 2-cohort, machine learning study.

BACKGROUND: Brain imaging is of limited diagnostic use in psychiatry owing to clinical heterogeneity and low sensitivity/specificity of between-group neuroimaging differences. Machine learning (ML) may better translate neuroimaging to the level of individual participants. Studying unaffected offspring of parents with bipolar disorders (BD) decreases clinical heterogeneity and thus increases sensitivity for detection of biomarkers. The present study used ML to identify individuals at genetic high risk (HR) for BD based on brain structure. METHODS: We studied unaffected and affected relatives of BD probands recruited from 2 sites (Halifax, Canada, and Prague, Czech Republic). Each participant was individually matched by age and sex to controls without personal or family history of psychiatric disorders. We applied support vector machines (SVM) and Gaussian process classifiers (GPC) to structural MRI. RESULTS: We included 45 unaffected and 36 affected relatives of BD probands matched by age and sex on an individual basis to healthy controls. The SVM of white matter distinguished unaffected HR from control participants (accuracy = 68.9%, p = 0.001), with similar accuracy for the GPC (65.6%, p = 0.002) or when analyzing data from each site separately. Differentiation of the more clinically heterogeneous affected familiar group from healthy controls was less accurate (accuracy = 59.7%, p = 0.05). Machine learning applied to grey matter did not distinguish either the unaffected HR or affected familial groups from controls. The regions that most contributed to between-group discrimination included white matter of the inferior/middle frontal gyrus, inferior/middle temporal gyrus and precuneus. LIMITATIONS: Although we recruited 126 participants, ML benefits from even larger samples. CONCLUSION: Machine learning applied to white but not grey matter distinguished unaffected participants at high and low genetic risk for BD based on regions previously implicated in the pathophysiology of BD.

The effectiveness of prefrontal theta cordance and early reduction of depressive symptoms in the prediction of antidepressant treatment outcome in patients with resistant depression: analysis of naturalistic data.

Current studies suggest that an early improvement of depressive symptoms and the reduction of prefrontal theta cordance value predict the subsequent response to antidepressants. The aim of our study was (1) to compare the predictive abilities of early clinical improvement defined as ≥ 20 % reduction in Montgomery and Åsberg Depression Rating Scale (MADRS) total score at week 1 and 2, and the decrease of prefrontal theta cordance at week 1 in resistant depressive patients and (2) to assess whether the combination of individual predictors yields more robust predictive power than either predictor alone. Eighty-seven subjects were treated (≥ 4 weeks) with various antidepressants chosen according to the judgment of attending psychiatrists. Areas under curve (AUC) were calculated to compare predictive effect of defined single predictors (≥ 20 % reduction in MADRS total score at week 1 and 2, and the decrease of cordance at week 1) and combined prediction models. AUCs of all three predictors were not statistically different (pair-wise comparison). The model combining all predictors yielded an AUC value 0.91 that was significantly higher than AUCs of each individual predictor. The results indicate that the combined predictor model may be a useful and clinically meaningful tool for the prediction of antidepressant response in patients with resistant depression.

An interplay between cross-cultural and psychometric factors in the Montreal Cognitive Assessment: Experience from the language of a small nation.

The present study aimed to test the hypothesis that the total word length on the Memory subtest of the Czech version of the MoCA, which is 12 syllables compared to the English version of 7 syllables, would have a significant effect on Delayed Recall scores compared to the newly created well-balanced version of the test (further MoCA-WLE). In the original Czech version of MoCA, we replaced the 12-syllable word list in the Memory subtest with a 7-syllable list (MoCA-WLE) to make it equivalent to the standard English version in this respect. We analyzed data from 83 participants in the original MoCA group (70.63 ± 7.01 years old, 14.61 ± 3.17 years of education, 30.12% males) and 83 participants in the MoCA-WLE group (70.72 ± 6.95 years old, 14.93 ± 3.48 years of education, 30.12% males). We did not find evidence for a significant word-length effect in the original MoCA versus MoCA-WLE Delayed Recall in either the Mann-Whitney U test (W = 3418.0, p = .932) or multilevel binomial regression (b = 0.10, 95% posterior probability interval [-0.46, 0.68]). The present study shows cross-cultural limits in the adaptation of the test material. The results underline the caveats of such an approach to test adaptation. Fortunately, 12-syllables in the MoCA Memory Czech version versus the original 7-syllable list did not show a detectable word-length effect. We did not find evidence for differential item functioning or cultural item bias. The original MoCA Czech version is psychometrically comparable to the original English version.

Small effects of olfactory identification and discrimination on global cognitive and executive performance over 1 year in aging people without a history of age-related cognitive impairment.

Olfactory and cognitive performance share neural correlates profoundly affected by physiological aging. However, whether odor identification and discrimination scores predict global cognitive status and executive function in healthy older people with intact cognition is unclear. Therefore, in the present study, we set out to elucidate these links in a convenience sample of 204 independently living, cognitively intact healthy Czech adults aged 77.4 ± 8.7 (61-97 years) over two waves of data collection (one-year interval). We used the Czech versions of the Montreal Cognitive Assessment (MoCA) to evaluate global cognition, and the Prague Stroop Test (PST), Trail Making Test (TMT), and several verbal fluency (VF) tests to assess executive function. As a subsidiary aim, we aimed to examine the contribution of olfactory performance towards achieving a MoCA score above vs. below the published cut-off value. We found that the MoCA scores exhibited moderate associations with both odor identification and discrimination. Furthermore, odor identification significantly predicted PST C and C/D scores. Odor discrimination significantly predicted PST C/D, TMT B/A, and standardized composite VF scores. Our findings demonstrate that olfaction, on the one hand, and global cognition and executive function, on the other, are related even in healthy older people.

Antidepressant monotherapy compared with combinations of antidepressants in the treatment of resistant depressive patients: a randomized, open-label study.

OBJECTIVE: This randomized, 6-week, open-label study compared efficacy of CAD and antidepressant monotherapies (ADM) that had been chosen according to clinical judgment of the attending psychiatrist. METHODS: A total of 60 inpatients (intent-to-treat analysis) with depressive disorder (≥ 1 unsuccessful antidepressant treatment) were randomly assigned to the interventions. The responders who completed the acute phase of study, were evaluated for relapse within 2 months of follow-up treatment. The primary outcome measure was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) and response was defined as a ≥ 50% reduction of MADRS score. RESULTS: Mean changes in total MADRS score from baseline to week 6 for patients in both treatment modalities were not different (ADM = 13.2 ± 8.6 points; CAD = 14.5 ± 9.5 points; P = 0.58). The analysis of covariance performed for significantly higher value of imipramine equivalent dose in CAD group showed only a non-significant between-group difference for total MADRS change (P = 0.17). There were also no differences between groups in response rate (ADM = 48%; CAD = 58%) and number of drop-outs in acute treatment as well as proportion of responders' relapses in the follow-up. CONCLUSION: Both treatment modalities produced clinically relevant reduction of depressive symptomatology in acute treatment of patients with resistant depression and their effect was comparable.

Processing speed predicts SuperAging years later.

BACKGROUND: SuperAging is one of the current concepts related to elite, resilient or high-functioning cognitive aging. The main aim of our study was to find possible predictors of SuperAgers (SA). METHODS: Community-dwelling older persons (N = 96) aged 80-101 years in 2018 were repeatedly tested (year 2012 and 2018). SA were defined based on their performance in 2018 as persons of 80+ years of age who recalled ≥ 9 words in the delayed recall of the Philadelphia Verbal Learning Test, and had a normal performance in non-memory tasks [the Boston Naming Test, the Trail Making Test Part B, and Category Fluency ("Animals")], which was defined as a score within or above one standard deviation from the age and education appropriate average. Three composite scores (CS; immediate memory, processing speed, and executive functions) were created from the performance in 2012, and analysed as possible predictors of SA status in 2018. RESULTS: We identified 19 SA (15 females) and 77 nonSA (42 females), groups did not significantly differ in age, years of education, and sex. The logistic regression model (p = 0.028) revealed three predictors of SA from the baseline (year 2012), including processing speed (p = 0.006; CS-speed: the Prague Stroop Test-Dots and the Digit Symbol Substitution Test), sex (p = 0.015), and age (p = 0.045). CONCLUSIONS: Thus, SA may be predicted based on the level of processing speed, which supports the hypothesis of the processing speed theory of healthy aging.

Reducing misclassification of mild cognitive impairment based on base rate information from the Uniform data set.

The current study aimed to define and validate the criteria for characterizing possible and probable cognitive deficits based on the psychometric approach using the Uniform data set Czech version (UDS-CZ 2.0) to reduce the rate of misdiagnosis. We computed the prevalence of low scores on the 14 subtests of UDS-CZ 2.0 in a normative sample of healthy older adults and validated criteria for possible and probable cognitive impairment on the sample of amnestic Mild Cognitive Impairment (MCI) patients. The misclassification rate of the validation sample using psychometrically derived criteria remained low: for classification as possible impairment, we found 66-76% correct classification in the clinical sample and only 2-8% false positives in the healthy control validation sample, similar results were obtained for probable cognitive impairment. Our findings offer a psychometric approach and a computational tool to minimize the misdiagnosis of mild cognitive impairment compared to traditional criteria for MCI.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment.

OBJECTIVE: Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li). METHODS: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction. RESULTS: The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls. CONCLUSIONS: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis.

BACKGROUND: Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li). METHODS: To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models. RESULTS: Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respectively), which had smaller left and right hippocampal volumes than the control group (Cohen d = -0.36, 95% CI -0.55 to -0.17; Cohen d = -0.38, 95% CI -0.63 to -0.13, respectively). There was no evidence of publication bias. LIMITATIONS: Missing information about the illness burden or lifetime exposure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses. CONCLUSION: When exposure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consistent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants.