scholarly journals PAX-D: study protocol for a randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression

2021 ◽  
pp. ebmental-2021-300282
Author(s):  
Sheena Kristine Au-Yeung ◽  
James Griffiths ◽  
Sophie Roberts ◽  
Chloe Edwards ◽  
Ly-Mee Yu ◽  
...  
Keyword(s):  
Decision Making ◽  
Depressive Symptomatology ◽  
Bipolar Depression ◽  
Antidepressant Medication ◽  
Well Being ◽  
Reward Processing ◽  
Self Report ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

IntroductionClinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task.Methods and analysisPAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties.DiscussionPramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD.Trial registration numberISRCTN84666271

scholarly journals Pharmacological Treatments for Patients with Treatment-Resistant Depression

2020 ◽  
Vol 13 (6) ◽  
pp. 116 ◽  
Author(s):  
Valerie L. Ruberto ◽  
Manish K. Jha ◽  
James W. Murrough
Keyword(s):  
Treatment Options ◽  
Symptom Relief ◽  
Antidepressant Medication ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Qualitative Synthesis ◽  
Course Of Illness ◽  
Effective Strategies ◽  
Increased Risk ◽  
Resistant Depression

Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk of suicide. Next step treatment options for patients with TRD, include switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another (non-antidepressant) medication. It is unclear which of these treatment approaches should be applied to a given patient, and in what order. Due to this ambiguity, comparing antidepressants and augmentation agents on the basis of their efficacy, tolerability, and speed of symptom relief would be beneficial for clinicians. To accomplish this, a systematic search was conducted following PRISMA guidelines. Only randomized controlled trials were included in this qualitative synthesis, resulting in 66 articles. This review identified several effective pharmaco-therapeutic strategies that are currently available for patients with TRD. Ketamine and esketamine appear to be effective for the treatment of TRD. Augmentation with certain second generation antipsychotics, such as quetiapine or aripiprazole is likewise effective, and may be preferred over switching to antidepressant monotherapy. While the combination of olanzapine and fluoxetine was one of the first pharmacotherapy approved for TRD, and its use may be limited by metabolic side-effects. Other effective strategies include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants including bupropion, tricyclics, or mirtazapine. There is insufficient research to demonstrate the efficacy of ziprasidone or levothyroxine (T4). A shared decision-making approach is recommended to guide treatment selection to address each patient’s individual needs.

Treatments for Pediatric Depression

2015 ◽  
Author(s):  
Carolina Biernacki ◽  
Prerna Martin ◽  
Pablo H. Goldberg ◽  
Moira A. Rynn
Keyword(s):  
Positive Response ◽  
Behavioral Therapy ◽  
Antidepressant Medication ◽  
Psychosocial Interventions ◽  
Evidence Base ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Medication Treatment ◽  
Pediatric Depression ◽  
Resistant Depression

Practice guidelines recommend psychosocial interventions for mild or brief cases of pediatric depression. In moderate to severe cases, medication treatment is recommended, with or without cognitive-behavioral therapy (CBT). Fluoxetine and escitalopram are the only antidepressants approved by the U.S. Food & Drug Administration for acute pediatric depression. Among psychosocial interventions, CBT and interpersonal psychotherapy for adolescents (IPT-A) have the largest evidence base for treatment of depressed youth. Combination treatment with CBT and antidepressant medication is superior to treatment with either modality alone. In treatment-resistant depression, a switch in antidepressant is more likely to yield a positive response when medication is used with CBT. Antidepressants should be used judiciously in youths as higher rates of adverse events have been demonstrated, and data from adult trials cannot be systematically extrapolated to youths. Further studies are needed to assess alternative medication and psychosocial treatments as well as factors predictive of treatment response.

scholarly journals Use of 30-Hz Accelerated iTBS in Drug-Resistant Unipolar and Bipolar Depression in a Public Healthcare Setting: A Case Series

2022 ◽  
Vol 12 ◽  
Author(s):  
Filippo Cantù ◽  
Giandomenico Schiena ◽  
Domenico Sciortino ◽  
Lorena Di Consoli ◽  
Giuseppe Delvecchio ◽  
...  
Keyword(s):  
Rating Scale ◽  
Bipolar Depression ◽  
Case Series ◽  
Healthcare Setting ◽  
Public Healthcare ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Depressive Episodes ◽  
Hamilton Rating Scale

Background: Depressive episodes, especially when resistant to pharmacotherapy, are a hard challenge to face for clinicians and a leading cause of disability worldwide. Neuromodulation has emerged as a potential therapeutic option for treatment-resistant depression (TRD), in particular transcranial magnetic stimulation (TMS). In this article, we present a case series of six patients who received TMS with an accelerated intermittent theta-burst stimulation (iTBS) protocol in a public healthcare setting.Methods: We enrolled a total number of six participants, affected by a treatment-resistant depressive episode, in either Major Depressive Disorder (MDD) or Bipolar Disorder (BD). Patients underwent an accelerated iTBS protocol, targeted to the left dorsolateral prefrontal cortex (DLPFC), 3-week-long, with a total of 6 days of overall stimulation. On each stimulation day, the participants received 3 iTBS sessions, with a 15-min pause between them. Patients were assessed by the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Anxiety (HAM-A), and the Mania Rating Scale (MRS). At baseline (T0), at the end of the second week (T1), and at the end of the cycle of stimulation (T2).Results: The rANOVA (repeated Analysis of Variance) statistics showed no significant effect of time on the rating scale scores, with a slight decrease in MADRS scores and a very slight increase in HAM-A and HAM-D scores. No manic symptoms emerged during the entire protocol.Conclusions: Although accelerated iTBS might be considered a less time-consuming strategy for TMS administration, useful in a public healthcare setting, our results in a real-word six-patient population with TRD did not show a significant effect. Further studies on wider samples are needed to fully elucidate the potential of accelerated iTBS protocols in treatment-resistant depression.

scholarly journals Use of Ketamine to Treat Depressive Symptoms in Schizoaffective Disorder

2019 ◽  
pp. 271-274
Author(s):  
Isaac Freedman ◽  
Daniel Rabin ◽  
Prabhneet Pannu ◽  
Tariq Bandoo ◽  
Bal Nandra ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
Growth Factor ◽  
Schizoaffective Disorder ◽  
Bipolar Depression ◽  
Synaptic Connections ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Complex Disorders ◽  
Resistant Depression ◽  
Psychotic Features

The use of subanesthetic ketamine infusions in treatment resistant depression and bipolar depression is becoming more common. Subanesthetic doses of ketamine cause the patient to dissociate, which was initially considered a side effect of this treatment; it is believed to play a role in a patient’s clinical improvement. Researchers attribute this result to an increase in brain-derived neurotrophic factor, a growth factor that stimulates the formation of new synaptic connections. Due to its psychogenic affect, ketamine treatment is less suitable for patients who experience mood disorders with psychotic features. Although symptomatic hallucinations seemingly conflict with the dissociative effects of ketamine, treatment of a patient with depressive type schizoaffective disorder revealed significant improvements in his depressive symptoms, demonstrating ketamine’s potential to be safely administered to patients with a variety of complex disorders.

scholarly journals Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

2021 ◽  
Vol 12 ◽  
Author(s):  
Alina Wilkowska ◽  
Mariusz Stanisław Wiglusz ◽  
Maria Gałuszko-Wegielnik ◽  
Adam Włodarczyk ◽  
Wiesław Jerzy Cubała
Keyword(s):  
Depressive Symptoms ◽  
Depressive Episode ◽  
Controlled Trial ◽  
Self Report ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Antidepressive Effect ◽  
Resistant Depression ◽  
Depression Symptomatology

Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient's lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.

scholarly journals Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

2017 ◽  
Vol 7 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Sarah E. Grady ◽  
Travis A. Marsh ◽  
Allison Tenhouse ◽  
Kelsey Klein
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Bipolar Depression ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Major Depressive ◽  
Randomized Controlled ◽  
The Past ◽  
Aspartate Receptor ◽  
Resistant Depression

Abstract Introduction: Over the past decade, ketamine has been studied for major depressive disorder and bipolar depression. Ketamine is believed to exert its antidepressant properties through N-methyl-D-aspartate receptor antagonism. Methods: Study authors completed a literature review of seven randomized controlled trials of ketamine usage in major depressive disorder and bipolar depression. Results: Ketamine demonstrated a statistically significant improvement over placebo or midazolam in major depressive disorder. Ketamine also exhibited a statistically significant improvement over placebo in bipolar depression. Discussion: Ketamine has shown promise in quickly reducing symptoms in patients with treatment resistant depression and bipolar depression. Using ketamine may be helpful for patients that have exhausted other therapeutic options.

An Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine

2020 ◽  
Vol 20 (7) ◽  
pp. 554-584 ◽  
Author(s):  
Domenico De Berardis ◽  
Carmine Tomasetti ◽  
Maurizio Pompili ◽  
Gianluca Serafini ◽  
Federica Vellante ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Depressive Symptomatology ◽  
Phase Iii ◽  
Glutamatergic Neurotransmission ◽  
Treatment Resistant Depression ◽  
Glutamatergic System ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Imminent Risk

Background: A research on mood disorder pathophysiology has hypothesized abnormalities in glutamatergic neurotransmission, by suggesting further investigation on glutamatergic N-methyl-Daspartate (NMDA) receptor modulators in treating Major Depressive Disorder (MDD). Esketamine (ESK), an NMDA receptor antagonist able to modulate glutamatergic neurotransmission has been recently developed as an intranasal formulation for treatment-resistant depression (TRD) and for rapid reduction of depressive symptomatology, including suicidal ideation in MDD patients at imminent risk for suicide. Objective: The present study aims at investigating recent clinical findings on research on the role of the glutamatergic system and ESK in treating suicidal depression in MDD and TRD. Methods: A systematic review was here carried out on PubMed/Medline, Scopus and the database on U.S. N.I.H. Clinical Trials (https://clinicaltrials.gov) and the European Medical Agency (EMA) (https://clinicaltrialsregister.eu) from inception until October 2019. Results: Intravenous infusion of ESK is reported to elicit rapid-acting and sustained antidepressant activity in refractory patients with MDD and TRD. In phase II studies, intranasal ESK demonstrated a rapid onset and a persistent efficacy in patients with TRD as well as in MDD patients at imminent risk for suicide. However, some data discrepancies have emerged in phase III studies. Conclusion: The U.S. Food and Drug Administration (FDA) granted fast track and Breakthrough Therapy Designation to Janssen Pharmaceuticals®, Inc. for intranasal ESK in 2013 for treatment-resistant depression (TRD) and in 2016 for the treatment of MDD with an imminent risk of suicide. However, further studies should be implemented to investigate the long-term efficacy and safety of intranasal ESK.

scholarly journals Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression

2021 ◽  
Vol 11 ◽  
pp. 204512532110110
Author(s):  
Adam Włodarczyk ◽  
Wiesław J. Cubała ◽  
Maria Gałuszko-Węgielnik ◽  
Joanna Szarmach
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Small Sample Size ◽  
Small Sample ◽  
Mood Stabilizers ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

Background: There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine’s safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP). Methods: A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol. Results: No antidepressants were associated with psychomimetic symptomatology except for citalopram ( p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed. Conclusions: Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients. ClinicalTrials.gov identifier: NCT04226963

scholarly journals Comparison of hypothalamo-pituitary-adrenal function in treatment resistant unipolar and bipolar depression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalypso Markopoulou ◽  
Susanne Fischer ◽  
Andrew Papadopoulos ◽  
Lucia Poon ◽  
Lena J. Rane ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Bipolar Depression ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Total Cortisol ◽  
The Awakening ◽  
Resistant Depression ◽  
Symptom Patterns ◽  
Hpa Axis Activity ◽  
First Time

AbstractAltered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this study was to test, for the first time, whether post-awakening cortisol, a highly reliable, naturalistic measure of HPA functioning, could distinguish patients with clearly defined treatment-resistant unipolar (TRUD) and bipolar depression (TRBD). A total of 37 patients with TRUD, 17 patients with TRBD, and 47 healthy controls were recruited. Areas under the curve (AUC) with respect to the ground (g) and increase (i) of post-awakening cortisol concentrations (awakening, +15, +30, +45, +60, +90 min) were measured over two days. Patients with TRUD had higher total cortisol production in the morning hours compared to controls (AUCg, p = 0.01), while they did not differ in terms of the awakening response (AUCi, p = 0.28). By contrast, subjects with TRBD had lower total cortisol when compared to controls by trend (AUCg, p = 0.07), while they did not differ in the awakening response (AUCi, p = 0.15). A direct comparison of TRUD and TRBD revealed differences in the AUCg (p = 0.003) and AUCi (p = 0.03). This finding of comparatively elevated HPA axis activity in the morning in TRUD and attenuated HPA axis activity in TRBD attests to a fundamental biological distinction between unipolar and bipolar depression. It has implications for the understanding and treatment of bipolar depression and in differentiating the two types of depression.

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