Objective
Although a relationship between schizophrenia (SCZ), antipsychotic (AP) medication, and metabolic dysregulation is now well established, the effect of adiposity is less well understood. By ...synthesizing findings from imaging techniques that measure adiposity, our systematic review and meta‐analysis (PROSPERO CRD42020192977) aims to determine the adiposity‐related effects of illness and treatment in this patient population.
Methods
We searched MEDLINE, EMBASE, PsychINFO and Scopus for all relevant case‐control and prospective longitudinal studies from inception until February 2021. Measures of adiposity including percent body fat (%BF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed as primary outcomes.
Results
Our search identified 29 articles that used imaging methods to quantify adiposity among patients with SCZ spectrum disorders. Analyses revealed that patients have greater %BF (mean difference (MD) = 3.09%; 95% CI: 0.75–5.44), SAT (MD = 24.29 cm2; 95% CI: 2.97–45.61) and VAT (MD = 33.73 cm2, 95% CI: 4.19–63.27) compared to healthy controls. AP treatment was found to increase SAT (MD = 31.98 cm2; 95% CI: 11.33–52.64) and VAT (MD = 16.30 cm2; 95% CI: 8.17–24.44) with no effect on %BF. However, change in %BF was higher for AP‐free/AP‐naïve patients compared to treated patients.
Conclusion
Our findings indicate that patients with SCZ spectrum disorders have greater adiposity than healthy controls, which is increased by AP treatment. Young, AP‐naïve patients may be particularly susceptible to this effect. Future studies should explore the effect of specific APs on adiposity and its relation to overall metabolic health.
Background
Gamma‐Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. ...Clozapine, the only approved drug for treatment‐resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1H‐MRS), and clozapine response in patients with TRS.
Methods
This study enrolled patients with TRS who did not respond to clozapine (ultra‐resistant schizophrenia: URS) and who responded to clozapine (non‐URS), patients with schizophrenia who responded to first‐line antipsychotics (first‐line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1H‐MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups.
Results
A total of 98 participants (URS: n = 22; non‐URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non‐URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group.
Conclusion
Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.
Objective
Clozapine is presently the sole antipsychotic with an indication for treatment‐resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This ...retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine‐induced weight gain.
Methods
We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes.
Results
Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine‐only group at 6 months (clozapine+metformin: −0.15 kg SE = 1.08 vs. clozapine‐only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: −0.67 kg, SE = 1.22 vs. clozapine‐only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only.
Conclusion
In this large retrospective naturalistic cohort study, co‐prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine‐induced weight gain; larger randomized controlled trials are needed to confirm these results.
The neurotransmitter dopamine is present in the retina and is involved in several modulatory functions. Unlike in rodents, dopamine D3 receptors are expressed in the retina of humans. Recently, ...uptake of the D3 receptor‐preferring radiotracer 11C‐(+)‐PHNO has been observed in a retina‐like region of interest (ROI) in humans. Here, we attempted to quantify 11C‐(+)‐PHNO uptake into this ROI using an independent sample, employing an extended scan acquisition time (120 min) and arterial kinetic modeling. Data from 14 healthy controls were analyzed (Mean Age: 38.41 ± 9.55, 3 female), 8 of which provided arterial line input function data (Mean Age: 41.07 ± 7.82, 3 female). Using Ichise's multilinear analysis (MA1) method, it was possible to quantify the volume of distribution (VT) of 11C‐(+)‐PHNO in this retina‐like region (Mean VT = 13.56 ± 3.52; Mean χ2 = 2.08 ± 2.20). Notably, the shape of the time activity curve resembled closely that of the globus pallidus. Moreover, the VT values in the retina correlated well with binding potential (BPND) values calculated using the simplified reference tissue model (Mean BPND = 2.11 ± .94; Mean χ2 = 5.76 ± 2.56), employing the cerebellum as the reference region (r = .76, r2 = .58). In summary, we provide evidence that the in vivo uptake of 11C‐(+)‐PHNO into a retina‐like ROI in humans can be quantified using both arterial blood sampling (VT) and simplified reference tissue methods (BPND).
11C‐(+)‐PHNO shows a significant uptake into a retina‐like region in humans
This uptake could be quantified with arterial and reference tissue methods
With this tracer, it may be possible to measure dopamine receptor availability in the retina
Aim
Validating the vulnerabilities and pathologies underlying treatment‐resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting ...neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS.
Methods
We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first‐line antipsychotics (FL‐Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ‐Resp) and 22 FL‐ and clozapine‐resistant patients (patients with ultratreatment‐resistant schizophrenia URS). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis.
Results
Both CLZ‐Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g gH = 0.75; P = 0.013, gH = 0.96) and FL‐Resp (P = 0.007, gH = 1.00; P = 0.002, gH = 1.31) in the left medial parietal cortex (Lt‐MPC). In addition, both CLZ‐Resp and URS had lower SA in the Lt‐MPC than FL‐Resp (P < 0.001, gH = 1.22; P < 0.001, gH = 1.75). LGI and SA were positively correlated in non‐TRS (FL‐Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ‐Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non‐TRS versus TRS with LGI and SA in the Lt‐MPC were 0.79 and 0.85, respectively. SA in the Lt‐MPC was inversely correlated with negative symptoms (ρ = −0.40, P = 0.018) and clozapine plasma levels (ρ = −0.35, P = 0.042) in TRS.
Conclusion
LGI and SA in the Lt‐MPC, a functional hub in the default‐mode network, were abnormally reduced in TRS compared with non‐TRS. Thus, altered LGI and SA in the Lt‐MPC might be structural features associated with genetic vulnerability to TRS.
Novel coronavirus disease 2019 (COVID-19) vaccine hesitancy is a barrier to achieving herd immunity, and thus, a prominent public health concern. This study aimed to identify the determinants of ...COVID-19 vaccine hesitancy based on the World Health Organization's '3Cs' model (i.e., confidence, complacency, and convenience) in the United States (U.S.) and Canada. Data from 7678 adults ages 18 or older were collected from the four most populous U.S. States, specifically New York, California, Florida, and Texas, and from English-speaking Canada at three timepoints, in May and July 2020, and March 2021 using a web-based survey (www.covid19-database.com). Sociodemographic information was collected, and comprehensive psychological assessments were administered. Univariate analyses were performed to identify the individual determinants of vaccine hesitancy, which were categorized as: 1) vaccine confidence, 2) vaccine complacency, 3) sociodemographic, and 4) other psychological factors. A series of models were computed using these categorizations. Mistrust of vaccine benefit (beta(SE) = 0.67(0.01), p<0.001, partial eta.sup.2 = 0.26) and lower perceived seriousness of COVID-19 (beta(SE) = 0.68(0.02), p<0.001, partial eta.sup.2 = 0.12) were the principal determinants of vaccine hesitancy. Right-wing political affiliation (beta(SE) = 0.32(0.02), p<0.001, partial eta.sup.2 = 0.03), higher risk propensity (beta(SE) = 0.24(0.02), p<0.001, partial eta.sup.2 = 0.03), and less negative mental health effects of the COVID-19 pandemic (beta(SE) = 0.20(0.01), p<0.001, partial eta.sup.2 = 0.03) were the main sociodemographic and psychological determinants. Other sociodemographic determinants included younger age, women, race, and employment status. Lack of vaccine confidence and complacency explained 38% and 21% of the variance in vaccine hesitancy, respectively; whereas, sociodemographic and psychological determinants explained 13% and 11% of the variance in vaccine hesitancy, respectively. Targeted and tailored public health interventions that enhance the public's confidence in vaccines and emphasize the risk and seriousness of COVID-19 may address COVID-19 vaccine hesitancy. Efforts directed toward specific marginalized and underserved groups may be required to promote vaccine confidence.
Despite the high prevalence of anxiety in schizophrenia, no established guideline exists for the management of these symptoms. We aimed to synthesize evidence on the effect of second-generation ...antipsychotics (SGAs) on anxiety in patients with schizophrenia.
We systematically searched Medline, Embase, PsycInfo, Web of Science, PubMed, and Cochrane library to identify randomized controlled trials of SGAs that reporting anxiety measures in schizophrenia. The search was limited to English-language articles published before February 2024. Data were pooled using a random-effects model.
Among 48 eligible studies, 29 (n = 7712) were included in the meta-analyses comparing SGAs to placebo, haloperidol, or another SGAs for their effect on anxiety/depression. SGAs had a small effect on anxiety/depression versus placebo (SMD = −0.28 (95 % CI −0.34, −0.21, p < .00001, I2 = 47 %, n = 5576)) associated with efficacy for positive (z = 5.679, p < .001) and negative symptoms (z = 4.490, p < .001). Furthermore, SGAs were superior to haloperidol (SMD = −0.44, 95 % CI −0.75, −0.13, p = .005, n = 1068) with substantial study-level heterogeneity (I2 = 85 %). Excluding one study of quetiapine in first-episode patients (SMD = −3.05, n = 73), SGAs showed a small effect on anxiety/depression versus haloperidol without heterogeneity (SMD = −0.23, 95 % CI −0.35, −0.12, p = 01; I2 = %0). Risperidone's effect on anxiety/depression was comparable to olanzapine (SMD = −0.02, 95 % CI −0.24,0.20, p = .87, I2 = 45 %, n = 753) and amisulpride (SMD = 0.27, 95 % CI −1.08,0.61, p = .13, I2 = 50 %, n = 315).
While SGAs showed a small effect on anxiety/depression, the findings are inconclusive due to scarcity of research on comorbid anxiety in schizophrenia, heterogeneity of anxiety symptoms, and the scales used to measure anxiety. Further studies employing specific anxiety scales are required to explore antipsychotics, considering their receptor affinity and augmentation with serotonin/norepinephrine reuptake inhibitors or benzodiazepines for managing anxiety in schizophrenia.
•We conducted the first meta-analysis on metabolite levels of kynurenine pathway in patients with depression.•Out of 899 initial records, 22 articles were identified.•Kynurenic acid and kynurenine ...levels are decreased in patients with depression.•Quinolinic acid levels are increased in unmedicated patients with depression.•Future research should examine relationships between treatment and kynurenine pathway.
Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.
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