Dataset Information

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

ABSTRACT:

Background

The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites.

Methods

Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups.

Results

Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate.

Conclusions

Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

SUBMITTER: Tani H

PROVIDER: S-EPMC10844359 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

Tani Hideaki H Moxon-Emre Iska I Forde Natalie J NJ Neufeld Nicholas H NH Bingham Kathleen S KS Whyte Ellen M EM Meyers Barnett S BS Alexopoulos George S GS Hoptman Matthew J MJ Rothschild Anthony J AJ Uchida Hiroyuki H Flint Alastair J AJ Mulsant Benoit H BH Voineskos Aristotle N AN

Brain imaging and behavior 20231102 1

<h4>Background</h4>The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites.<h4>Methods</h4>Following remission, patients with psychotic depression w ...[more]

PMID: 37917311

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Project description:To characterize the role of antipsychotic medications in the community treatment of adult depression. We identified adults (aged 18-64 years) with new episodes of depression treatment (ICD-9-CM 296.2, 296.3, 300.4, or 311) in US national Medicaid data (2001-2010). Patients with alternative ICD-9-CM antipsychotic indications, such as schizophrenia or bipolar disorder, were excluded. Each patient was followed for at least 1 year to characterize antipsychotic and antidepressant treatment and emerging alternative antipsychotic indications. For patients without alternative indications through day 45 following start of antipsychotic treatment, antipsychotics were considered to be intended for treatment of depression. Among this group, we determined whether antipsychotic initiation was preceded by minimally adequate treatment with antidepressants, defined as active antidepressant treatment for ≥ 31 days prior to and including the day of antipsychotic initiation. Within 1 year following onset, 14.0% of patients started an antipsychotic medication. A total of 41.3% of antipsychotic initiators developed an antipsychotic indication other than depression through day 45 following antipsychotic initiation, most often bipolar disorder or depression with psychotic features. The remaining 58.7% of antipsychotic initiators presumably started antipsychotics for nonpsychotic depression. Of these, 71.3% did not have minimally adequate antidepressant treatment prior to starting the antipsychotic medication. Antipsychotic medications are used in approximately 1 in 7 patients with a new episode of depression. For 1 in 12 patients, the antipsychotic was considered to be intended for nonpsychotic depression. Almost three-quarters of these patients did not receive minimally adequate treatment with antidepressants prior to antipsychotic initiation. This pattern suggests potentially inappropriate and premature initiation of a drug class with substantial adverse effects and medical risks.

Project description:ImportancePrescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question.ObjectiveTo assess the effects of antipsychotics on brain structure in humans.Design, setting, and participantsPrespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019.InterventionsThose who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse.Main outcomes and measuresThe primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter.ResultsEighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission.Conclusions and relevanceIn this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness.Trial registrationClinicalTrials.gov Identifier: NCT01427608.

Project description:BACKGROUND:Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. OBJECTIVES:To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. SELECTION CRITERIA:Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. DATA COLLECTION AND ANALYSIS:Working independently, we critically appraised records from 681studies, of which five studies met inclusion criteria. John Rathbone from the Schizophrenia Group supported us with the data extraction. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. MAIN RESULTS:Five studies with a combined N = 998 met inclusion criteria. Four studies (N = 724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs N = 353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT N = 240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT N = 236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT N = 94, RR 0.96 CI 0.3 to 3.6). Two studies (Cole 1964; May 1976) contributed data to assessment of side effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. Rappaport 1978 suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (N = 80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non-significant in a sensitivity analysis on intent-to-treat participants (N = 127, RR 1.69 CI 0.9 to 3.0). One study (May 1976) contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (N = 92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One study (Mosher 1995) contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (N = 89, MD 0.01 CI -0.6 to 0.6) and global improvement (N = 89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. AUTHORS' CONCLUSIONS:With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.

Dataset Information

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

Background

Methods

Results

Conclusions

Publications

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

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