Resistant Depressed Patients Research Articles

Interventional approaches to treatment resistant depression (DTR) in children and adolescents: A systematic review and meta-analysis

BackgroundMajor depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. MethodsFollowing PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10–24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. ResultsMeta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92–3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04–2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79–4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. ConclusionsThis meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed.

Effect of intermittent theta-burst stimulation on the thyroid and adrenal systems in resistant depressed patients

IntroductionDisturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently reported in treatment resistant depressed patients (TRDs). So far, the effects of intermittent theta-burst stimulation (iTBS) treatment—a form of repetitive transcranial magnetic stimulation (rTMS) technique—on the activity of the HPT and HPA axes are poorly understood.ObjectivesThe present study aimed to evaluate the effects of iTBS sessions, applied to the left dorsolateral prefrontal cortex, in TRDs with abnormal chronobiological HPT functioning at baseline (BL) possibly associated with hypercortisolemia.MethodsThe ∆∆TSH test (i.e., the difference between the thyrotropin response to protirelin tests [∆TSH] performed at 8 AM and 11 PM on the same day) and the dexamethasone suppression test (DST) were performed in 12 TRDs and 14 healthy hospitalized control subjects (HCs). To be enrolled in this study, patients had to show at BL reduced ∆∆TSH values (i.e., &lt; 2.5 mU/L) and a score of 18 or greater on the 17-item Hamilton Rating Scale for Depression (HAMD-17). Post-DST cortisol maximum (CORmax) serum level in excess of 120 nmol/L defined DST non-suppression (i.e., hypercortisolemia)—6 TRDs were DST non-suppressors at BL. After 10 and 20 iTBS sessions the ∆∆TSH test and the DST were repeated in all inpatients. A positive clinical response was defined by a final HAMD-17 score ≤ 8.ResultsCompared to HCs, ∆∆TSH values were lower in TRDs at BL (p &lt; 0.00001), and remained reduced after 10 and 20 iTBS sessions (p &lt; 0.001 and p &lt; 0.02 respectively). Post-DST CORmax levels were higher in TRDs than in HCs at BL (p &lt; 0.01), but were comparable to those of HCs after 10 and 20 iTBS sessions. Responders (n = 5) were characterized by 1) a normalization of their ∆∆TSH values after 20 iTBS sessions (whereas after 10 iTBS sessions ∆∆TSH values were still reduced compared to HCs [p &lt; 0.05]), and 2) a normality of post-DST CORmax levels at BL—while after 10 and 20 iTBS sessions post-DST CORmax levels were decreased compared to HCs (p &lt; 0.006 and p &lt; 0.03 respectively). Non-responders (n = 7) showed 1) no significant change in their ∆∆TSH values which remained lower than those of HCs at each assessment (all p &lt; 0.001), 2) while increased post-DST CORmax levels found at BL (p &lt; 0.0008 vs. HCs) normalized from the 10th iTBS session.ConclusionsThe present pilot study suggests that successful iTBS treatment can restore the chronobiological activity of the HPT axis. Although iTBS may increase glucocorticoid receptor signaling, baseline hypercortisolemia could negatively impact subsequent response to iTBS treatment.Disclosure of InterestNone Declared

Cariprazine add-on in resistant bipolar depression. Long-term effectiveness and safety data from a multicentric real-world experience

IntroductionPersistent depressive episodes and subsyndromic depressive symptoms frequently characterize mood alterations in bipolar disorder (BD) and negatively influence quality of life and suicide risk. BD patients with predominant depressive episodes generally show significantly higher treatment resistance rates. Although not specifically approved in Italy for bipolar depression, recently published observational data suggest that the cariprazine add-on may be a potential effective short-term treatment for resistant bipolar depression. Nevertheless data on long-term cariprazine treatment are lacking.ObjectivesThis study evaluated the efficacy and safety of long-term cariprazine augmentation in patients suffering from treatment-resistant bipolar depression.Methods30 resistant bipolar depressed patients, whose resistance was defined according to The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder, were treated with cariprazine 1,5 -3 mg flexible dose for 4 weeks, added to previous mood stabilizing and/or antidepressant treatment. Psychopathology at time 0 and at 4, 8, 12, 16, 20, 24 weeks of treatment was evaluated using the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Young Mania Rating Scale (YMRS) and the Bipolar Depression Rating Scale (BDRS); safety and tolerability was measured by the UKU Side Effect Rating Scale. The drop-out rate was assessed throughout the study duration.ResultsCariprazine add-on was effective in the study sample but only during the first 4 weeks of treatment. Improvement in depression scores started from the first week, reaching about 40% mean HDRS score reduction at T4; a moderate ulterior decrease (-15%) was reached at T24 but was accompanied by a significant drop-out rate; anxiety symptoms improved (mean HARS score reduction 37% at T4) mainly during the first 4 weeks. The treatment was generally well tolerated. From week 4 to 24 we observed a near 70% drop-out rate (18 total drop-outs) with maximum drop-outs between weeks 4-8 (n=7) and 18-24 (n=7). Discontinuation causes were inefficacy (5/18); clinical worsening (10/18); side effects (3/18); hypomanic shift (2/18).ConclusionsDespite the relatively small population examined and the observational design, our results suggest that cariprazine may represent an effective and safe short-term enhancement strategy in resistant bipolar depression. Long-term treatment, in this sample, did not lead to significant improvements and was burdened by a high drop-out rate, mainly due to inefficacy/clinical worsening. Further studies on larger samples are needed to confirm these preliminary findings, both in short-term and in longer observations.Disclosure of InterestNone Declared

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

Treatment-Resistant Depression in America Latina study: one-year follow-up of treatment resistant depression patients under standard of care reveals insights on quality of life, disability, work impairment, and depressive symptoms.

Depressive Disorders are on the rise worldwide. This is also the case in Latin America (LatAm). Treatment-Resistant Depressive Disorder (TRD) poses additional burden to patients with depression. Impacts quality of life (QoL) and other dimensions, and standard of care (SOC) is insufficient to achieve the desired clinical outcomes. Evidence from LatAm is, however, lacking. The present study was devised as a 1-year follow-up of the SOC in TRD patients in LatAm to explore the burden of TRD. This was an observational, multinational, longitudinal study. Patients with clinical diagnosis of TRD in LatAm were included in a 1-year follow-up with SOC. Beyond the Sociodemographic characterization, outcome measures were QoL (EQ-5D-5L), disability (Sheehan Disability Scale - SDS), work productivity (Work Productivity and Activity Incapacity Questionnaire: depression - WPAI:D) and depression severity (Patient Health Questionnaire-PHQ9). Patients were assessed every 3-months and comparison was performed based on change from baseline to each visit and end of study (EOS - 12 months). Patients averaged 48 (± 13.12) years, mostly female (80.9%) and married/consensual union (42.5%) or single patients (34.4%). Despite the SOC treatment, three-quarters of the patients remained symptomatic at EOS, regardless of the significant longitudinal decrease (p ≤ 0.001). Similar trends were found for disability (p ≤ 0.001) -82.2% of the patients reporting work/school disruption at EOS-, percentage of work (34%) and activity impairment (40%) at EOS (p ≤ 0.001) and only 29.2% of patients with depressive severity "none" at EOS (p ≤ 0.001). The results portray the need to improve clinical outcomes in this complex and burdensome disease in LatAm. Here we show that the burden of TRD remains significant in essential dimensions of everyday life at EOS underlining the need for better therapeutic solutions. The improvements in most patients do not provide the desired outcome of return to the state before the condition. Further research should focus on identifying which treatments provide better outcomes in a real-world context.

Elevated Matrix Metalloproteinase 9 in Treatment Resistant Bipolar Depression

Objective: Matrix metalloproteinase is a family of proteases with different pathophysiological roles. Matrix metalloproteinase 9 (MMP9) plays an enzymatic role in the restructuring of the extracellular matrix and adhesion molecules. MMP9 is upregulated in pro-inflammatory states and leads to breakdown of tight junctions thereby increasing blood-brain barrier (BBB) permeability. MMP9 may contribute to the pathophysiology of bipolar disorder (BD) via proteolysis of the BBB thus allowing entry of cytokines and neurotoxic agents into CNS. Polymorphisms of the MMP9 gene may pose increased risk for BD and schizophrenia. In this study we sought to determine MMP9 levels in treatment resistant bipolar depressed patients before and after treatment.&#x0D; Methods: Treatment resistant bipolar depressed patients were treated with escitalopram, in combination with the COX-2 inhibitor, celecoxib. It was hypothesized that combination treatment would reverse resistance and augmented treatment responses. This was a 10-week, randomized, double-blind, two-arm, placebo-controlled study.&#x0D; Results: MMP9 levels were higher in bipolar depressed patients compared to healthy controls at baseline, however, the difference did not reach significance. Levels decreased after treatment reaching significance in the escitalopram plus placebo group. Female patients had significantly lower MMP9 levels at end of treatment. MMP9 was higher in carriers the MMP9 SNP, rs3918242, than in noncarriers, but the difference did not reach statistical significance.&#x0D; Conclusion: MMP9 decreased in bipolar depressed patients with treatment. Age, sex and the rs3918242 polymorphism play a role in MMP9 levels. Future studies should confirm the role of MMP9 in the pathogenesis and pathophysiology of bipolar disorder, as a potential diagnostic biomarker.

Cariprazine add-on for resistant bipolar depression: preliminary results from an italian real-world experience

IntroductionDepressive episodes represent the most frequent mood alteration in bipolar disorder (BD). Persistent depressive episodes and subsyndromic depressive symptoms often lead to poor quality of life and increase suicide risk. Recent studies have also shown that BD patients with a history of predominant depressive episodes generally show poorer response to pharmacological treatments. Although not specifically approved in Italy for use in bipolar depression, the scientific literature produced so far suggests the possible use of cariprazine in clinical conditions of bipolar depression that do not respond to conventional treatments.ObjectivesThe aim of the study was to evaluate, in a real-world multicentric Italian clinical setting, the efficacy and safety of cariprazine augmentation strategy in a sample of patients suffering from treatment-resistant bipolar depression.Methods16 resistant bipolar depressed patients, whose resistance was defined according to The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder, were observed for 4 weeks after the add-on to previous mood stabilizing treatment of a cariprazine 1,5 mg fixed dose. Psychopathology at time 0 and at 1, 2, 3, and 4 weeks of treatment was evaluated using the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Young Mania Rating Scale and the Brief Psychiatric Rating Scale; safety and tolerability of the therapy was measured by the UKU Side Effect Rating Scale.ResultsClinical improvement induced by 1,5 mg cariprazine add-on was effective and well tolerated in the study sample. Improvement in depression scores started from the first week, reaching about 35% reduction within 15 days and almost 50% in the following weeks (mean HDRS score from 24,7 to 13,2, GLM r.m. p&lt;0,001); global psychopathology improved (mean BPRS score from 29,9 to 15,3 GLM r.m. p&lt;0,001) as well as anxiety symptoms (mean HARS score from 26,5 to 16,5 GLM r.m. p=0,003). No manic shifts were observed during the observation period and the treatment was generally well tolerated.ConclusionsDespite the small number of patients examined and the short term of observation, cariprazine could represent an effective and safe enhancement strategy for patients with bipolar depression resistant to common pharmacological treatments. Further studies on larger samples are needed to confirm these preliminary findings. In addition, a more prolonged observation would be appropriate to highlight whether the beneficial effect of cariprazine add-on persists over time.Disclosure of InterestNone Declared

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients

MicroRNA changes after electroconvulsive therapy in treatment resistant depressed patients

microRNA changes after electroconvulsive therapy in treatment resistant depressed patients

Dietary Patterns of Treatment-Resistant Depression Patients.

Depression is a common mental disorder that occurs all over the world with treatment resistance commonly seen in clinical practice. Ketamine exhibits an antidepressant that is more often used in the case of treatment-resistant depression (TRD) in MDD and BP. Research emphasizes that a healthy diet and the nutrients it contains can lower the risk of developing depression and form a strategy that supports conventional treatment. The aim of the study was to evaluate the patients’ diet and to analyze the effect of ketamine on food intake among patients with TRD. The study involved 15 patients suffering from treatment-resistant depression and 15 healthy volunteers. The data required for the analysis were collected using the food frequency questionnaire (FFQ) and 4-day food diaries. The study group was statistically significantly less likely to consume milk and plain milk beverages, plain white cheese, wholemeal bread, various vegetables, wine, and drinks. Our results show several disorders in the eating habits of patients with treatment–resistant depression. After the administration of ketamine, the patients consumed significantly less protein, fats, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), fiber, tryptophan, vitamins, and minerals compared to the control group. There is a lack of research describing the effects of ketamine on nutrition. In order to confirm the results of the study, more participants are required, and the assessment of food diaries filled in at the patient’s home with a longer interval after the last dose of ketamine as well.

ESKALE study, a French real-world study of esketamine nasal spray for patients with treatment-resistant depression

IntroductionEsketamine nasal spray has been developed to treat adults with treatment resistant depression. On Dec.2019, EMA granted a market access approval in this indication.ObjectivesESKALE is a descriptive study of treatment resistant depression patients treated with esketamine in France.MethodsObservational retrospective study. 157 patients are included in 3 cohorts depending on their treatment initiation date. This abstract presents the second interim results of patients treated with esketamine and whom data collection ranges from Oct.2019 and Sept.2021.Results66.7% of patients were females. Average age was 49 years old with 26 patients &gt; 65 years old. Duration of the current depressive episode was 26.0 months (mean). 48.8% of patient have &gt; 1 suicide attempt during whole life. At esketamine initiation, 78.2% patients were clinically perceived to have severe depression with a MADRS score of 32.4 (median) and a PHQ9 score of 19.5 (median). For the overall sample, esketamine was prescribed in median as a 3rd line and for 40.5% of patients after neurostimulation. The majority of the patient started esketamine at 28 mg or 56 mg and increased the dose to 84 mg. After 4 months of treatment, clinical benefits are the following: decrease of MADRS total score -16.5 points (median) corresponding to 58% of responders and a PHQ9 total score decrease of -8.6 points (median). No new safety signal detected.ConclusionsThis second interim analysis describes patients’ profiles and clinical evolution over a longer period and a broader population than the first interim analysis. The conditions of use are consistent with the ones approved by health authorities.DisclosureI (Marie-Alix Codet) works as a full employee at Janssen Cilag

P292. Sex Differences in a Double-Blind Randomized Clinical Trial With Minocycline in Treatment-Resistant Depressed Patients: CRP and IL-6 as Sex-Specific Predictors of Treatment Response

The Minocycline in Depression (MINDEP) study is a 4-weeks double-blind, placebo-controlled clinical trial, investigating the efficacy of minocycline in treatment resistant depressed (TRD) patients with major depressive disorder, and C-reactive protein (CRP) ≥ 1mg/L.

Investigation of physical activity, sleep, and mental health recovery in treatment resistant depression (TRD) patients receiving repetitive transcranial magnetic stimulation (rTMS) treatment.

Repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression; however, the effect on physical activity, sleep and recovery is unclear. This study investigated rTMS effect on physical activity and sleep through providing patients with a Fitbit and software apps; and reports the impact of rTMS on depression, anxiety and mental health recovery. Study design was a pre and post data collection without a control, with twenty-four participants with treatment-resistant depression (TRD). Measures used were Fitbit activity and sleep data, and patient-rated Recovering Quality of Life (ReQoL-20), Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder (GAD-7). Response and remission rates were, respectively: 34.8% and 39% for PHQ-9; 34.8% and 47.8% for GAD-7. ReQoL-20 response and reliable improvement were 29.4% and 53%. PHQ-9, GAD-7 and ReQol-20 scores significantly improved, with large effect sizes. Analysis of Fitbit activity and sleep data yielded non-significant results. The Fitbit data machine learning model classified two levels of depression to 82% accuracy. rTMS treatment was open-label and adjunct to existing antidepressant medication. No control group. Female patients were overrepresented. Improvements on the ReQoL-20 and aspects of sleep and activity indicate the positive impact of rTMS on the individual's real world functioning and quality of life. A wearable activity tracker can provide feedback to patients and clinicians on sleep, physical activity and depression levels. Further research could be undertaken through a sufficiently powered RCT comparing rTMS versus rTMS with use of a Fitbit, its software applications, and sleep and physical activity advice.

Power signatures of habenular neuronal signals in patients with bipolar or unipolar depressive disorders correlate with their disease severity

The habenula is an epithalamic structure implicated in negative reward mechanisms and plays a downstream modulatory role in regulation of dopaminergic and serotonergic functions. Human and animal studies show its hyperactivity in depression which is curtailed by the antidepressant response of ketamine. Deep brain stimulation of habenula (DBS) for major depression have also shown promising results. However, direct neuronal activity of habenula in human studies have rarely been reported. Here, in a cross-sectional design, we acquired both spontaneous resting state and emotional task-induced neuronal recordings from habenula from treatment resistant depressed patients undergoing DBS surgery. We first characterise the aperiodic component (1/f slope) of the power spectrum, interpreted to signify excitation-inhibition balance, in resting and task state. This aperiodicity for left habenula correlated between rest and task and which was significantly positively correlated with depression severity. Time-frequency responses to the emotional picture viewing task show condition differences in beta and gamma frequencies for left habenula and alpha for right habenula. Notably, alpha activity for right habenula was negatively correlated with depression severity. Overall, from direct habenular recordings, we thus show findings convergent with depression models of aberrant excitatory glutamatergic output of the habenula driving inhibition of monoaminergic systems.

Sex differences in a double-blind randomized clinical trial with minocycline: pilot findings on the key role of the immune system in treatment-resistant depressed female patients

The Minocycline in Depression (MINDEP) study is a 4-weeks double-blind, placebo-controlled clinical trial, investigating the efficacy of minocycline in treatment resistant depressed (TRD) patients with major depressive disorder, and C-reactive protein (CRP) ≥ 1 mg/L. We explored sex differences in the effects of study arms and CRP groups (CRP ≥ 3 mg/L; CRP < 3 mg/L) on HAMD-17 variation from baseline to week-4. Independent samples t-test detected a significant difference between minocycline (M) and placebo (PL) groups only in males but not females, with M group (N=8) showing greater improvement in comparison with PL group (N=9) (p=0.046). However, M female group with CRP ≥ 3 mg/L (N=3) showed the greatest clinical improvement in comparison with the other female groups (p<0.05 vs. all groups). General linear model univariate analysis confirmed the significant interaction between study arms and CRP groups in females (p=0.005). These pilot findings suggest that TRD male patients may benefit from minocycline add-on treatment independently of their baseline inflammatory levels, while TRD female patients may benefit from minocycline only if having higher baseline inflammatory levels.

Evaluation of major depression symptom networks using clinician-rated and patient-rated data

BackgroundMajor depressive disorder (MDD) is heterogeneous, but official diagnostic classifications and widely used rating scales are based on the premise that MDD is a single disorder and that symptoms are equally important to assess severity. Also, patients and clinicians frequently diverge in how they evaluate MDD severity. In order to better understand the differences between MDD scales used by clinicians and patients in the context of MDD heterogeneity, we performed a network analysis from an approach that focuses on the interaction of symptoms rather than total score. MethodsThe Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory with 21 items (BDI) scored by the clinician or patient, respectively, were used to estimate the networks based on 794 MDD patients. The networks were estimated using software R 4.0.2 and Graphical Lasso, identifying communities of symptoms by the clique percolation method, and the mixed graphical models were used to evaluate the explained variance of each symptom. ResultsThe networks presented different communities of symptoms and connection structure (M = 0.177, p = 0.0028). The guilt connection strength and its association with suicidal ideation was greater in the BDI network. LimitationsTransversal data from severe, chronic, or treatment resistant depression patients. ConclusionsThe present study suggests that the self-rated scale may perform better when assessing association between guilt and other symptoms, especially suicidal ideation. Communities of symptoms and edges between symptoms suggest that insomnia may be an independent symptom, thus requiring specific interventions. Some similar items are strongly connected and could be collapsed.

Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials

Background: Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. Methods: The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. Results: The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Discussion: Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. Clinical trial registration: UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).

P.258 Depression and suicidal ideation in treatment resistant depression patients in Latin America: final results from the multicentre, prospective, observational TRAL study

Somatostatin (SST) mediates cytostatic and pro-apoptotic effects through five somatostatin receptors (SSTR1-5). The modest clinical benefits of SST analogs in cancers of different origin such as breast cancer are attributed to diminished SSTRs expression at tumor sites. In the present study, SSTR3 was overexpressed in MCF-7 and MDA-MB-231, and analyzed for downstream signaling molecules associated with cytostatic and cytotoxic effect. Cells overexpressing SSTR3 displayed inhibition of EGF induced proliferation and enhanced antiproliferative effect of SSTR3-specific agonist in comparison to non-transfected cells. SSTR3 overexpression in MCF-7 cells (R3-MCF-7) constitutively enhanced TUNEL staining, PARP-1 and p27Kip1 expression suggesting apoptosis and cell-cycle arrest. Conversely, R3-MB-231 cells with SSTR3 overexpression exerted cytostatic and were devoid of any cytotoxic effects. The expression of PTP-1C and the status of ERK1/2, p38 and PI3K phosphorylation was modulated in a cell-specific manner. These findings provide new insights in understanding the antiproliferative role of SSTR3 in breast tumor biology.

Adjunctive treatment with psychostimulants and stimulant-like drugs for resistant bipolar depression: a systematic review and meta-analysis.

Depression is considered to be the most difficult to treat phase of bipolar disorder as patients experience residual symptoms causing long-term disability. This work aims to explore the role of add-on stimulant and stimulant-like medication in resistant bipolar depression patients. Systematic review of add-on stimulants and stimulant-like drugs in resistant bipolar depression by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Analysis was performed using the random-effects models. Heterogeneity was evaluated with Cochran's Q and I2 statistics. Six randomized controlled trials of add-on modafinil, armodafinil, and lisdexamphetamine (LDX) (n=813) vs placebo (n=815) in the treatment of resistant bipolar depression were included. These drugs were more likely to induce remission from an episode of resistant bipolar depression (relative risk [RR]=1.37; 95% confidence interval [CI]: 1.06-1.77; number needed to treat for an additional beneficial outcome=16). Moreover, they did not induce more dropouts than placebo (RR=1.04; 95% CI: 0.91-1.18), nor did they increase the risk of adverse effects (53/772 vs 41/771) at the end of treatment (RR=1.30; 95% CI: 0.81-2.10; number needed to treat for an additional harmful outcome=62). Suicidality and manic switch were not affected by active treatment. Heterogeneity was low (Cochran's Q: P>.05), but sometimes with a large CI. LDX, modafinil, and armodafinil seem to offer a reasonably well-tolerated and safe treatment in resistant bipolar depression. Treatment guidelines should, therefore, be revised to include these medications earlier in the therapeutic algorithm for resistant acute bipolar depression. Further research is, however, necessary for the elucidation of the clinical usefulness of these and other similar compounds.

Protracted Effects of Ketamine Require Immediate Kappa Opioid Receptor Activation and Long‐Lasting Desensitization

Ketamine produces rapid and sustained antidepressant activity, but its mechanism of action remains uncertain. Williams &amp; colleagues (2018) reported that naltrexone pretreatment attenuated ketamine’s effects in treatment resistant depressed patients. Naltrexone antagonizes both kappa (KOR) and mu opioid receptors (MORs). We hypothesized that ketamine requires acute KOR activation, leading to long‐lasting suppression of KOR signaling to exert its antidepressant effects. The following series of experiments demonstrated: 1) exposure to ketamine produces internalization of KORs; 2) the behavioral effects of ketamine in mice were prevented by prior KOR blockade; and 3) ketamine pretreatment prevented behavioral and physiological responses caused by subsequent KOR activation.KOR internalization was tested in HEK293 cells transfected with yPET‐OPRK1 plasmids following ketamine stimulation (2 μM). Approximately 30% of KORs were internalized, which was comparable to the internalization achieved with the endogenous KOR agonist dynorphin (40 μM). To demonstrate that activation of KORs by ketamine contributes to its protracted behavioral profile, C57BL/6J mice (8–12 weeks) were pretreated with naltrexone (1 mg/kg) or the selective KOR antagonist LY2444296 (3 mg/kg) 30 minutes prior to ketamine (10 mg/kg) and were tested in the forced swim test 24 h later. Reductions in immobility scores by ketamine were blocked by naltrexone and LY2444296 pretreatment, confirming the importance of KORs in initiating ketamine’s long‐lasting effects.Next, the physiological impact of ketamine on KOR activity was examined ex vivo in the lateral habenula (LHb), a reward‐related brain region. Bath application of the KOR agonist U50,488 (10 μM) robustly increased the number of action potentials in response to depolarization. The increase in LHb neuronal excitability was absent when ketamine (10 mg/kg) was administered to mice 24 h previously. In parallel, U50,488 (10 or 20 mg/kg) induced behavioral deficits on nest building, prepulse inhibition and antinociception on the hot plate were effectively prevented by ketamine (10 or 20 mg/kg) given 24 h earlier. Finally, LY2444296 (3 mg/kg) administered 30 min prior to ketamine (10 mg/kg) prevented ketamine‐induced suppression of U50,488‐induced alterations on nesting behavior 24 h later. This established that KOR occupation prior to ketamine prevented the initiation of ketamine’s long‐lasting behavioral effects.Collectively, these studies provide evidence supporting the hypothesis that activation of KORs by acute ketamine administration leads to enduring reductions of KOR signaling, which may contribute to the protracted clinical antidepressant effects of ketamine.Support or Funding InformationThis work was funded by US Public Health Service (USPHS) grant R01 MH105623.