Treatment Of Bipolar Depression Research Articles

Home-based transcranial direct current stimulation in bipolar depression: an open-label treatment study of clinical outcomes, acceptability and adverse events

BackgroundCurrent treatments for bipolar depression have limited effectiveness, tolerability and acceptability. Transcranial direct current stimulation (tDCS) is a novel non-invasive brain stimulation method that has demonstrated treatment efficacy for major depressive episodes. tDCS is portable, safe, and individuals like having sessions at home. We developed a home-based protocol with real-time remote supervision. In the present study, we have examined the clinical outcomes, acceptability and feasibility of home-based tDCS treatment in bipolar depression.ResultsParticipants were 44 individuals with bipolar disorder (31 women), mean age 47.27 ± 12.89 years, in current depressive episode of at least moderate severity (mean Montgomery Asberg Depression Rating Scale (MADRS) score 24.59 ± 2.64). tDCS was provided in bilateral frontal montage, F3 anode, F4 cathode, 2 mA, for 30 min, in a 6-week trial, for total 21 sessions, a follow up visit was conducted 5 months from baseline. Participants maintained their current treatment (psychotherapy, antidepressant or mood stabilising medication) or maintained being medication-free. A research team member was present by video conference at each session. 93.2% participants (n = 41) completed the 6-week treatment and 72.7% of participants (n = 32) completed the 5 month follow up. There was a significant improvement in depressive symptoms following treatment (mean MADRS 8.77 ± 5.37) which was maintained at the 5 month follow up (mean MADRS 10.86 ± 6.90), rate of clinical response was 77.3% (MADRS improvement of 50% or greater from baseline), and rate of clinical remission was 47.7% (MADRS rating of 9 or less). Acceptability was endorsed as “very acceptable” or “quite acceptable” by all participants. No participants developed mania or hypomania.ConclusionsIn summary, home-based tDCS with real-time supervision was associated with significant clinical improvements and high acceptability in bipolar depression. Due to the open-label design, efficacy findings are preliminary.Trial registrationClinicalTrials.gov number NCT05436613 registered on 23 June 2022 https//www.clinicaltrials.gov/study/NCT05436613.

Mania Associated With Cariprazine: A Case Report and a Review of Literature Regarding Bipolar Depression Treatment With Cariprazine.

Mania Associated With Cariprazine: A Case Report and a Review of Literature Regarding Bipolar Depression Treatment With Cariprazine.

Treatment-emergent symptoms during short-term ketamine administration in treatment-resistant bipolar depression: A retrospective cross-sectional descriptive study

Symptoms that emerge during pharmacological treatment of bipolar depression are frequently observed, underscoring the necessity for comprehensive treatment monitoring. This observational study sought to observe the correlation of eight intravenous ketamine infusions with treatment-emergent depressive symptoms in treatment-resistant bipolar depression patients who maintained their baseline psychotropic and chronic somatic treatments. Depressive symptoms were evaluated using the Inventory of Depressive Symptomatology Self-Report 30 (IDS-SR30). Treatment-emergent symptoms TES were defined as symptoms absent at baseline but present at the conclusion of the study. The most common TES included decreased appetite, increased weight, hypersomnia, and diurnal mood variation. Conversely, feelings of sadness, altered perceptions of the future, decreased interest in sex, and physical discomfort were absent in all patients. Notably, 13.6 % of patients reported thoughts of death or suicide. Larger-scale studies, integrating clinician-rated and patient-reported outcome measures, are essential to deepen our understanding of treatment-emergent symptoms. Establishing regulatory or professional definitions for treatment-emergent symptoms is warranted to improve the robustness of future research endeavors.

Treatment of bipolar depression: clinical practice vs. adherence to guidelines-data from a Bavarian drug surveillance project.

Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered ≥4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials shouldbeconducted in the future to prospectively investigate different implementation strategies.

Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain.

Nonracemic amisulpride (SEP-4199) is aninvestigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

Right ventrolateral and left dorsolateral 10 Hz transcranial magnetic stimulation as an add-on treatment for bipolar I and II depression: a double-blind, randomised, three‐arm, sham-controlled study

Objectives Despite the clinical importance of bipolar depression (BDE), effective treatment options are still limited. Transcranial magnetic stimulation (rTMS) has proven of moderate efficacy in major depression, but the evidence remains inconclusive for BDE. Methods A 4-week, double-blind, randomised, parallel-group, sham-controlled study (trial ID ISRCTN77188420) explored the benefits of 10 Hz MRI-guided right ventrolateral (RVL) rTMS and left dorsolateral (LDL) rTMS as add-on treatments for BDE. Outcome measures included changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, self-assessment, response and remission rates, and side effects. Results Sixty patients were randomly assigned to study groups, and forty-six completed the double-blind phase. The mean change from baseline to Week 4 in MADRS was greater in both active groups compared to the sham, yet differences did not achieve significance (RVL vs sham: −4.50, 95%CI −10.63 to 1.64, p = 0.3; LDL vs sham: −4.07, 95%CI −10.24 to 2.10, p = 0.4). None of the other outcome measures yielded significant results. Conclusions While not demonstrating the superiority of either 10 Hz rTMS over sham, with the limited sample size, we can not rule out a moderate yet clinically meaningful effect. Further well-powered studies are essential to elucidate the role of rTMS in managing BDE.

Hypomania with Low-Dose Lamotrigine Suggests it Really is an Antidepressant

Depression predominates over any other mood phases in bipolar I disorder, and treatment options remain sparse. Lamotrigine, an anticonvulsant used for the prevention and treatment of bipolar depression, has been reported to induce hypomanic and manic switches. Its multimodal mechanism of action may provide an explanation for its propensity to induce mood switches. The authors report a case of hypomania developing briefly after the introduction of very low-dose adjunctive lamotrigine for the treatment of bipolar depression and review proposed mechanisms of action.

Efficacy of Theta Burst Stimulation in Bipolar Depression: A Systematic Review and Meta-analysis

Purpose: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative therapeutic modality for bipolar depression. Theta Burst Stimulation (TBS) a novel variant of rTMS is currently evolving as an effective and safe therapeutic tool in the management of bipolar depression, although it is still in the initial phase. In the present systematic review and meta-analysis, data from various studies investigating the effectiveness and tolerability of TBS in individuals with bipolar depression were synthesized. Data collection and analyses: Eight studies assessing the efficacy of TBS as a treatment for bipolar depression were included after a systematic search. The quality of the included studies was assessed using standard methods. Synthesized data included three uncontrolled clinical trials (non-randomized controlled trials [RCTs]; n = 48) and five RCTs ( n = 201). While four studies used intermittent TBS, two studies used continuous TBS and bilateral TBS, each. Data from the five RCTs meta-analyzed using the random effects model showed the pooled odds ratio and effect size for response in the active group compared to the sham group were 1.01 (95%CI: 0.56, 1.83) and 1.64 (95%CI: –0.46, 3.74), respectively. Although both models showed no/minimal heterogeneity or publication bias, they were not statistically significant. A supplementary trial sequential analysis confirmed the need for more studies and suggested that the total sample required for drawing meaningful inferences was 918 samples. Conclusion: The available evidence suggests that more studies are required to draw conclusive inferences for the efficacy of TBS in the therapeutic management of bipolar depression.

Real-world retrospective study of repetitive transcranial magnetic stimulation (TMS) treatment for bipolar and unipolar depression using TMS registry data in Tokyo

Despite the prevalence of empirical practice, evidence supporting the use of repetitive transcranial magnetic stimulation (rTMS) in treating bipolar depression (BD) is sparse compared to that for unipolar depression. Therefore, this study aimed to conduct a retrospective observational analysis using TMS registry data to compare the efficacy of rTMS treatment for BD and unipolar depression. Data from 20 patients diagnosed with unipolar and BD were retrospectively extracted from the TMS registry to ensure age and sex matching. The primary outcomes of this registry study were measured using the 21-item Hamilton Depression Rating Scale (HAM-D21) and Montgomery−Åsberg Depression Rating Scale (MADRS). Analysis did not reveal significant differences between the two groups in terms of depression severity, motor threshold, or stimulus intensity at baseline. Similarly, no significant differences were observed in absolute or relative changes in the total HAM-D21 and MADRS scores. Furthermore, the response and remission rates following rTMS treatment did not differ significantly between groups. The only adverse event reported in this study was scalp pain at the stimulation site; however, the incidence and severity were not significantly different between the groups. In conclusion, this retrospective study, using real-world TMS registry data, suggests that rTMS treatment for BD could be as effective as that for unipolar depression. These findings underscore the need for further validation in prospective randomized controlled trials with larger sample sizes.

Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

Bipolar affective disorder occurring with psychopharmacotherapy-induced manic phases

To analyze the stages of development of the problem, identify the evolution of views and the main directions of current research in the field of bipolar affective disorder, which occurs with psychopharmacotherapy-induced manic phases, the search for publications by keywords «pharmaco-induced mania»", «bipolar affective disorder» was carried out in the PubMed/MEDLINE, Russian Citation index and other sources from the mid-19th century to the present. The issue of adequate treatment of bipolar depression became relevant back in the 20th century; numerous observations indicated the presence of associated risks when using antidepressants in patients with bipolar affective disorder, namely, the likelihood of affect inversion and aggravation of the course of the disease (accelerated cyclicity, continuum). In recent years, due to the expansion of research capabilities and the introduction of biological psychiatry, works have appeared that consider this problem from both clinical and pharmacodynamic, genetic and neurophysiological aspects, which opens up the prospect of developing advanced methods of personalized medicine for the diagnosis and treatment of bipolar disorder, taking into account the need to minimize iatrogenic effects.

Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis.

We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or≤10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.

Review finds seven drugs efficacious for treatment of bipolar depression

Review finds seven drugs efficacious for treatment of bipolar depression

Short-term ketamine use in bipolar depression: a review of the evidence for short-term treatment management.

Bipolar depression constitutes a major problem in psychiatry. It correlates with high suicidality, treatment resistance, chronicity, and poor quality of life. Registered treatment for bipolar depression is limited and insufficient. There is an urgent need for implementing new therapeutic strategies. Intranasal ketamine's enantiomer-esketamine is a novel rapid-acting antidepressant with proven efficacy in treatment-resistant depression. Research on bipolar depression, although not as comprehensive, indicates that it may be a viable and safe substitute with minimal risk for mood polarity changes. Reports suggest that ketamine treatment in bipolar depression may reduce suicidal tendencies, decrease anhedonia, and alleviate anxiety. Ketamine's mood-stabilizing properties are also hypothesized. In this narrative review, we focus on ketamine use as an add-on to standard medication for the acute treatment of bipolar depression.

Adjunctive antidepressants for the treatment of bipolar depression: An updated meta-analysis of randomized clinical trials

This updated meta-analysis aims to evaluate the efficacy of adjunctive antidepressants in the treatment of bipolar depression. The antidepressant group exhibited a significant increase in response rate (RR: 1.12; 95 % CI 1.01–1.25; p = 0.04; I2 =55 %). The pooled results demonstrated a significant increase in response rate in the antidepressant group (RR: 1.12 95 % CI 1.01–1.25, p = 0.04; I2 =55 %). Depression score was significantly lower in the antidepressant group (SMD: −0.20 95 % CI −0.31 to −0.09, p < 0.001; I2 =14 %). Egger’s regression test and funnel plot inspection did not suggest publication bias. Adjunctive antidepressants appear to enhance response rates and reduce depressive scores in bipolar depression, though potential biases and study heterogeneity warrant future randomized trials on this topic.

Exploring the potential of Esketamine in the treatment of bipolar depression

Exploring the potential of Esketamine in the treatment of bipolar depression

Lithium in bipolar depression: A review of the evidence.

Lithium is widely used as treatment of acute mania and as prophylactic therapy for bipolar disorder. International and national guidelines also consider lithium as a possible treatment of acute bipolar depression. Research on the use of lithium in bipolar depression, however, seems to be limited compared to the data available for its efficacy in the other phases of bipolar disorder. To provide a systematic review of the evidence for lithium in the treatment of acute bipolar depression and provide directions for further research. A systematic review of clinical studies investigating the use of lithium in bipolar depression was performed using preferred reporting items for systematic reviews and meta-analyses guidelines in Pubmed, Embase and Psychinfo using the medical subjects headings and free text terms "lithium," "bipolar depression," "dosage," "serum concentration" and "bipolar disorders." This review included 15 studies with a total of 1222 patients, between the age of 18 and 65, suffering from bipolar depression of which 464 were treated with lithium. There are currently only limited and low-quality data on the efficacy of lithium as a treatment of bipolar depression. It appears that there have been no placebo controlled randomized controlled trials with lithium concentrations that are considered to be therapeutic. The older studies suffered from limitations such as small sample sizes, insufficient treatment lengths, and insufficient monitoring of serum concentrations. In contrast to data for the treatment of mania and prophylaxis, robust data on the efficacy of lithium in bipolar depression is currently lacking, making it impossible to make conclusions regardingefficacy or inefficacy, for which further research is needed.

Effects of Exercise on Functional Recovery in Patients with Bipolar Depression: A Study Protocol for a Randomized Controlled Trial.

Treatment of bipolar disorder is prone to prolongation despite various treatments, including medication. The efficacy of exercise treatment (i.e., interventions involving physical exercise and sports intervention) for major depressive disorders has been reported for depressive symptoms, cognitive function, and sleep disturbances. However, its efficacy for bipolar disorder has yet to be established. We designed a randomized, controlled, double-blind clinical trial that includes 100 patients with bipolar disorder aged 20-65 years. This will be a cluster-randomized, two-group trial that will be conducted in ten psychiatric hospitals. The hospitals will be randomly assigned to an exercise intervention + treatment as usual (exercise) group or a placebo exercise intervention (stretching) + treatment as usual (control) group. Patients will be assessed using an extensive battery of clinical tests, physical parameters, sleep status, biological parameters (cytokines, neurotrophic factors), and genetic parameters (DNA and RNA) at baseline after a 6-week intervention period, at 10-week follow-up, and at 6-month follow-up. This innovative study may provide important evidence for the effectiveness of exercise in the treatment of bipolar depression based on clinical, biological, genetic, and physiological markers.

Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value.

The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Arketamine for bipolar depression: Open-label, dose-escalation, pilot study

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.