scholarly journals Esketamine and rapastinel, but not imipramine, have antidepressant-like effect in a treatment-resistant animal model of depression

2019 ◽  
Vol 31 (05) ◽  
pp. 258-265 ◽  
Author(s):  
Vitor Silva Pereira ◽  
Sâmia R.L. Joca ◽  
Brian H. Harvey ◽  
Betina Elfving ◽  
Gregers Wegener
Keyword(s):  
Forced Swim Test ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Repeated Treatment ◽  
Treatment Resistant Depression ◽  
Sprague Dawley ◽  
Treatment Resistant ◽  
Sprague Dawley Rats ◽  
Animal Model Of Depression ◽  
Resistant Depression

AbstractObjectives:Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals.Methods:Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out.Results:We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment.Conclusion:The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.

scholarly journals Role of the Pharmacist in Managing Treatment-Resistant Depression: A Focus on Ketamine

Pharmacy ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 118
Author(s):  
Linda Xing Yu Liu ◽  
Marina Golts ◽  
Virginia Fernandes
Keyword(s):  
Current Practice ◽  
Quality Care ◽  
Treatment Options ◽  
Critical Role ◽  
Transitions Of Care ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Multiple Treatments ◽  
The Impact

The impact of depression is well described in the literature, and it is most prominent in patients who have trialed multiple treatments. Treatment-resistant depression (TRD) is particularly debilitating, and it is associated with significant morbidity and mortality. Despite this, there seems to be therapeutic inertia in adopting novel therapies in current practice. Ketamine is an N-methyl-D-aspartate receptor antagonist and anesthetic agent which has recently been shown to be effective in the management of TRD when administered intravenously or intranasally. The treatments, however, are not easily accessible due to restrictions in prescribing and dispensing, high costs, and the slow uptake of evidence-based practice involving ketamine within the Canadian healthcare system. Given the limited treatment options for TRD, novel approaches should be considered and adopted into practice, and facilitated by a multi-disciplinary approach. Pharmacists play a critical role in ensuring access to quality care. This includes dissemination of evidence supporting pharmacological treatments and facilitating translation into current practice. Pharmacists are uniquely positioned to collaborate with prescribers and assess novel treatment options, such as ketamine, address modifiable barriers to treatment, and triage access to medications during transitions of care. Extending the reach of these novel psychiatric treatments in both tertiary and primary care settings creates an emerging role for pharmacists in the collaborative effort to better manage treatment-resistant depression.

scholarly journals Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance

2020 ◽  
Vol 30 (4) ◽  
pp. 261-266 ◽  
Author(s):  
Jeffrey R. Strawn ◽  
Scott T. Aaronson ◽  
Ahmed Z. Elmaadawi ◽  
G. Randolph Schrodt ◽  
Richard C. Holbert ◽  
...  
Keyword(s):  
Clinical Features ◽  
Treatment Resistance ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

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.

scholarly journals A case of treatment-resistant depression in an older adult and a discussion of treatment options

2021 ◽  
pp. 1-6
Author(s):  
Emma Pope ◽  
Sabari Muthukrishnan ◽  
James Phillips ◽  
Sarah Phillips
Keyword(s):  
Personal Experience ◽  
Treatment Options ◽  
Poor Response ◽  
Current Evidence ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Geriatric Population ◽  
Treatment Of Depression ◽  
Resistant Depression ◽  
Careful Assessment

Treatment-resistant depression is a complex condition often requiring specialist psychiatric care. Many different psychiatric, physical and social factors can lead to a poor response to initial treatment of depression, and a careful assessment is required to determine the most appropriate management option. This can be particularly complex in the older population, who often have multiple physical and social comorbidities. We have used a fictional case to illustrate this, alongside an anonymised vignette of someone with personal experience of this condition. We have also provided an overview of the current evidence for treatment options, as well as a discussion of potential aetiological factors. By the end of this article, readers should understand the ambiguity of this diagnostic term, the aetiological factors that need to be assessed and the rationale for the treatment options available. They should be able to recognise how these ideas apply to the geriatric population.

Therapeutic Strategies for Treatment-resistant Depression: State of the Art and Future Perspectives

2020 ◽  
Vol 26 (2) ◽  
pp. 244-252
Author(s):  
Kah K. Goh ◽  
Shen-Chieh Chang ◽  
Chun-Hsin Chen ◽  
Mong-Liang Lu
Keyword(s):  
Antidepressant Treatment ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Treatment Options ◽  
Therapeutic Strategies ◽  
Evidence Based ◽  
Inadequate Response ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Treatment Choices ◽  
Resistant Depression

In this narrative review, we intended to summarize the evidence of pharmacological and somatic treatment choices for treatment-resistant depression (TRD). There are several types of therapeutic strategies to improve inadequate response to antidepressant treatment. The first step for patients with TRD is to optimize the dosage and duration of antidepressants as well as to ensure their drug compliance. The shift to antidepressant and antidepressant combination therapy for patients with TRD cannot be regarded as an evidence-based strategy. Only the combination of a monoamine reuptake inhibitor with a presynaptic α2-autoreceptor antagonist might have better efficacy than other antidepressant combinations. Currently, the most evidence-based treatment options for TRD are augmentation strategies. Among augmentative agents, second-generation antipsychotics and lithium have the strongest evidence for the management of TRD. Further studies are needed to evaluate the augmentative efficacy of anticonvulsants, thyroid hormone, glutamatergic agents, anti-inflammatory agents, and nutraceuticals for TRD. Among somatic therapies, electroconvulsive therapy and repetitive transcranial magnetic stimulation are effective for TRD. Further studies are warranted to provide clinicians with a better recommendation in making treatment choices in patients with TRD.

scholarly journals Treatment-Resistant Depression Revisited: A Glimmer of Hope

2021 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Angelos Halaris ◽  
Emilie Sohl ◽  
Elizabeth A. Whitham
Keyword(s):  
Significant Risk ◽  
Treatment Resistance ◽  
Contributory Factor ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Test Procedures ◽  
Gonadal Dysfunction ◽  
Immune Biomarkers ◽  
Resistant Depression

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.

scholarly journals Diminished responses to monoaminergic antidepressants but not ketamine in a mouse model for neuropsychiatric lupus

2018 ◽  
Vol 33 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Bettadapura N Srikumar ◽  
Pattipati S Naidu ◽  
Narasimharaju Kalidindi ◽  
Mahesh Paschapur ◽  
Bharath Adepu ◽  
...  
Keyword(s):  
Wheel Running ◽  
Forced Swim Test ◽  
Sucrose Preference ◽  
Acute Administration ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Swim Test ◽  
Forced Swim ◽  
Immobility Time ◽  
Resistant Depression

Background: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression–like behavior. Aims: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. Methods and results: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies’ titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. Conclusion: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.

scholarly journals Transcranial pulsed electromagnetic fields for treatment-resistant depression: A multicenter 8-week single-arm cohort study

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Erik Roj Larsen ◽  
Rasmus W. Licht ◽  
René Ernst Nielsen ◽  
Annette Lolk ◽  
Bille Borck ◽  
...  
Keyword(s):  
Cohort Study ◽  
Antidepressant Treatment ◽  
Treatment Options ◽  
Depression Scale ◽  
Antidepressant Effect ◽  
Hamilton Depression Scale ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Pulsed Electromagnetic

Abstract Background. The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression. Methods. A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group. Results. In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4. Conclusions. The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

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