While theta burst stimulation (TBS) shows promise in Major Depressive Disorder (MDD), its effectiveness in bipolar depression (BD-D) remains uncertain. Optimizing treatment parameters is crucial in ...the pursuit of rapid symptom relief. Moreover, aligning with personalized treatment strategies and increased interest in immunopsychiatry, biomarker-based stratification of patients most likely to benefit from TBS might improve remission rates. We investigated treatment effectiveness of continuous TBS (cTBS) compared to sham in BD-D, and assessed the capacity of plasma kynurenine pathway metabolites to predict treatment outcome.
Thirty-seven patients with BD-D underwent accelerated active or sham cTBS treatment in a multicenter, double-blind, randomized controlled trial. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17) before treatment (T0), 3–4 days posttreatment (T1) and 10–11 days posttreatment (T2). Plasma tryptophan, kynurenine, kynurenic acid and quinolinic acid concentrations were quantified with ELISA. Linear mixed models were used for statistical analyses.
Although the total sample showed depressive symptom improvement, active cTBS did not demonstrate greater symptom alleviation compared to sham. However, higher baseline quinolinic acid significantly predicted symptom improvement in the active treatment group, not in sham-stimulated patients.
The modest sample size limited the power to detect significant differences with regard to treatment effect. Also, the follow-up period was 10–11 days, whereas similar studies usually follow up for at least one month.
More research is required to optimize cTBS for BD-D and explore the involvement of quinolinic acid in treatment outcome.
•cTBS for bipolar depression was not more effective than sham treatment.•Higher baseline plasma Quinolinic acid concentration predicted better cTBS outcome.•Patients had lower Quinolinic acid levels compared to healthy controls.
There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six ...subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart—0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.
•The mean MADRS total score prior to the infusion of 0.5 mg/kg of arketamine was 36.66, which dropped to 27.83 after 24h (p = 0.036).•The mean MADRS total score prior to a 1 mg/kg arketamine infusion was 32.0, which fell to 17.66 after 24h (p < 0.001).•The mean MADRS item 10 score prior to the infusion of 0.5 mg/kg of arketamine was 3.33, which dropped to 1.33 after 24h (p = 0.006).•There were no severe adverse effects reported for either dose, dissociation was nearly absent, and no manic symptoms were reported.•Further randomized, crossover, active placebo-controlled clinical trials with larger samples and longer follow-ups should be performed.
•Significant association between depression, anger and perceived stress.•Reduction in state and trait anger in responders to the combination of anti-inflammatory treatment.•Trait anger remained ...unchanged in the placebo add-on arm.•Significantly higher response and remission rates in depression scores in the celecoxib add-on arm compared to the placebo add-on arm.
: Anger can worsen a person's emotions and increase the severity of an individual's mood state, notably depression. The State-Trait Anger Expression Inventory (STAXI) assessment tool is useful for assessing the experience, expression, and control of anger in normal individuals, and in evaluating anger experienced by patients with a variety of psychological and medical disorders. Since its creation, STAXI has been utilized in various studies involving substance abuse and major depressive disorder; however, anger has never been studied systematically in bipolar depression. Scientific evidence supports the hypothesis that immune system activation, reflected in its inflammatory response, contributes to the pathophysiology and phenomenology of bipolar disorder. However, there is limited research showing how the treatment of bipolar disorder is enhanced with an anti-inflammatory agent and how it affects anger, which prompted this investigation. The current clinical study tested the hypothesis that co-administration of a specific anti-inflammatory agent, Celecoxib, along with Escitalopram, a selective serotonin reuptake inhibitor, would be beneficial in patients with treatment resistant bipolar depression. In comparison to patients receiving Escitalopram monotherapy, it was hypothesized that the combination therapy would lead to an augmented response in alleviating bipolar depression. In addition, the combination therapy would result in a greater percentage of responders and remitters. It also was hypothesized that the combination therapy would reduce anger symptoms as assessed by STAXI from beginning to end of treatment.
: In this double-blind, two-arm, placebo-controlled study, 65 consenting patients diagnosed with treatment resistant bipolar depression were randomized to receive either Escitalopram (10 mg twice/day) + Celecoxib (200 mg twice/day), or Escitalopram + placebo (twice/day). There were 47 completers: 27 in the Celecoxib, and 20 in the Placebo arm. The 17-item Hamilton Depression Rating Scale was used to assess response to treatment, with a 50% reduction from baseline indicating treatment response and a score < 7 indicating remission. The Beck Depression Index also was used as a self-report measure of depression. Levels of state and trait anger were assessed using the 57-item STAXI scale. Measures of depression, anger and perceived stress were collected at baseline and at week 8 of treatment.
: A multiple regression analysis of baseline data indicated that the Hamilton depression score was significantly related to the feelings subscale of the state STAXI. However, the baseline Beck score was found to be predicted by perceived stress. To test treatment effects, an analysis of covariance revealed that the week 8 Hamilton depression score was significantly lower for patients receiving the combination therapy, controlling for baseline differences. The week 8 Beck score also was lower for those in the combination therapy group, but was not statistically significant. In comparison to the monotherapy group, those receiving the combination therapy showed a statistically higher proportion of responders and remitters. Significant differences in state or trait anger subscales were found only responders to the CBX add-on arm at week 8.
: Limitations of the study include small sample size and short period of treatment.
: An analysis of baseline data suggest that depression is associated with state feelings of anger and perceived stress. In comparison to receiving Escitalopram alone, the combination therapy was more effective in lowering Hamilton depression scores and was associated with greater proportions of responders and remitters. Anti-inflammatory combination therapy reduced state and trait anger by the end of treatment.
To study differences in oxidative stress markers and antioxidants among patients with bipolar depression (BPD) and unipolar depression (UPD).
Data sources. Electronic MEDLINE/PubMed/Cochrane ...Library/Scopus/TripDatabase database search until 30/06/2021.
Study selection. Included were articles comparing antioxidant or oxidative stress markers between adults with BPD or UPD and healthy controls (HCs).
Data extraction. Two authors extracted data independently. Random effects meta-analysis, calculating standardized mean differences for results from ≥3 studies.
Oxidative stress markers reported in 40 studies −1 published repeatedly– (UPD, studies = 30 n = 3072; their HCs, n = 2856; BPD, studies = 11 n = 393; their HCs, n = 540; with 1 study reporting on both UPD and BPD) included thiobarbituric acid reactive substances (TBARS), antioxidant uric acid and antioxidant-enhancing enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GPX).
Compared with HCs, UPD and BPD were associated with significantly higher levels of TBARS, without differences between UPD and BPD (P = 0.11). Compared with HCs, UPD and BPD did not differ regarding the activity of the CAT (P = 0.28), SOD (P = 0.87) and GPX (P = 0.25) enzymes. However, uric acid levels were significantly higher vs HCs in BPD than in UPD among adult patients (P = 0.004). Results were heterogenous, which, for some parameters, decreased after stratification by the blood source (serum, plasma red blood cells, whole blood).
The main limitations are the small number of studies/participants in the BPD subgroup, and heterogeneity of the results.
Both BPD and UPD may be associated with an impaired oxidative stress balance, with significantly higher uric acid levels vs. HCs in UPD than in BPD.
•Both unipolar and bipolar depression showed an impaired oxidative stress balance•Compared with healthy controls, unipolar and bipolar depression showed higher levels of TBARS•Uric acid levels were significantly higher vs. healthy controls in bipolar than in unipolar depression•Compared with controls, unipolar and bipolar depression did not differ in TBARS and the activity of antioxidant enzymes
Objective: We reviewed important clinical aspects of bipolar depression, a progressive psychiatric condition that is commonly treated in primary care. Bipolar depression is associated with ...considerable burden of illness, high suicide risk, and greater morbidity and mortality than bipolar mania.
Methods: We identified articles relevant to our narrative review using a multistep search of the literature and applying terms that were relevant to bipolar depression or bipolar disorder.
Results: Bipolar depression accounts for the majority of time spent unwell for patients with bipolar disorder; high rates of morbidity and mortality arise from full symptomatic episodes and interepisode subsyndromal symptoms. Bipolar depression is an important contributor to long-term dysfunction for patients with bipolar disorder due to psychosocial impairment, loss of work productivity and high rates of substance abuse. Missed and delayed diagnosis is prevalent due to overlapping symptoms with unipolar depression and other diagnoses. Medical comorbidities (i.e. cardiovascular disease, hypertension, obesity, metabolic syndrome) and psychiatric comorbidities (i.e. anxiety disorder, personality disorder, eating disorder, attention-deficit/hyperactivity disorder) are common. Currently, only three treatments are FDA-approved for bipolar depression; monotherapy antidepressants are not a recommended treatment option.
Conclusions: Bipolar disorder is common among primary care patients presenting with depression; it is often treated exclusively in primary care. Clinicians should be alert for symptoms of bipolar disorder in undiagnosed patients, know what symptoms probabilistically suggest bipolar versus unipolar depression, have expertise in providing ongoing treatment to diagnosed patients, and be knowledgeable about managing common medication-related side effects and comorbidities. Prompt and accurate diagnosis is critical.
•Network-based statistics using a resting state functional connectivity.•Performance of graph theory analysis with whole-brain graph properties.•Investigation of brain network associated with a risk ...for bipolar disorder.•Classification for young depressed subjects at risk for developing bipolar disorder.
Major Depressive Disorder (MDD) is frequently associated with risk factors for the development of Bipolar Disorder (BD). Using graph theory, we investigated brain network properties associated with BD risk factors in young MDD subjects.
Resting-state fMRI was acquired from a large cohort (N= 104) of medication-free currently depressed participants (25 BD depression (BDD), 79 MDD). Lifetime mania symptom count (LMSC), current Young Mania Rating Scale (YMRS) score, and family history of mood disorders (FHMD) were examined as BD risk factors. Functional connectivity matrices from 280 regions of interests (ROIs) were first entered into the Network Based Statistic (NBS) toolbox to identify connections that varied with each risk factor. Next, within the correlated network for each risk factor, global and nodal graph properties for the top five linked nodes were calculated. Last, using identified graph properties, machine learning classification (MLC) between BDD, MDD with BD risk factors (MDD+), and without BD risk factors (MDD-) was conducted.
LMSC positively correlated with left lateral orbitofrontal cortex (LOFC) Communication Efficiency and with left middle temporal Eigenvector Centrality. Current YMRS score positively correlated with right amygdala Communication Efficiency and Closeness Centrality. FHMD positively correlated with right insula Eigenvector Centrality. Acceptable MLC accuracy was seen between BDD and MDD- using middle temporal Eigenvector Centrality, whereas moderate accuracy was seen between MDD+ and MDD- using OFC Communication Efficiency.
Although participants were medication-free, they were not medication-naïve.
Functional connectome graph properties may serve as BD vulnerability biomarkers in young individuals with MDD.
•Total sleep time and Sleep latency are impaired in all stages of Bipolar Disorder.•Increased REM density may precede the onset of the disease.•Microarchitecture is a poorly studied, especially sleep ...spindles.•Psychotic versus non-psychotic subjects and within-subject analyses are required.
Sleep disturbances are highly prevalent across all stages of Bipolar Disorder. Despite a wealth of research on the neurophysiological features of sleep in this population, progress in this field has been slow. We aimed to review the literature on sleep electroencephalography (EEG) studies in Bipolar Disorder, considering sleep architecture and microstructural oscillatory activity.
We included a total of 22 studies: six on sleep during manic episodes, seven during depressive episodes, seven in euthymic patients and two in high-risk individuals. The most consistent findings were increased SOL and REM density across all stages of the disorder. Only two studies reported a reduced spindle count during bipolar depression and euthymia, respectively. Although not specific for Bipolar Disorder, SOL and REM density have been repeatedly found to be increased across all stages of illness in this population. Whereas the former reflects a difficulty initiating sleep, the latter can be considered a neurophysiological signature of patients’ overall reduced sleep need, independent of illness stage.
•VEGF has been implicated in the neurotrophic model of depression.•Treatment resistant bipolar depression improves with adjunctive COX-2 inhibition.•Plasma VEGF is increased in bipolar depression ...similar to major depression.•Plasma VEGF may be a predictive biomarker for depression.•Baseline VEGF did not predict treatment response.
Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic model of depression. We explored the potential role of VEGF in the pathophysiology of bipolar depression and potential utility as a diagnostic or outcome predictive biomarker.
In a double-blind study, treatment-resistant bipolar depressed patients received Escitalopram and were randomized to receive add-on Celecoxib (26 participants) or Placebo (21 participants). There were 32 healthy controls. Plasma levels of VEGF were determined at three timepoints over eight weeks.
Bipolar patients had significantly higher VEGF levels at baseline compared to healthy controls. Logistic regression analysis revealed that the AUC is 0.67 and the VEGF cut point is 8.21. At all timepoints, patients receiving Celecoxib had comparable VEGF levels to those receiving Placebo. VEGF levels did not change significantly over time. Baseline VEGF was a poor predictor of treatment response with an AUC of 0.53.
The increased VEGF in bipolar depression agrees with similar findings in major depressive disorder. A high VEGF level tended to accurately predict bipolar disorder, with apparent differential VEGF expression. Baseline VEGF did not predict treatment response, and levels did not change with treatment. Plasma VEGF may have diagnostic utility and guide personalized treatment.
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