Treatment-Resistant Depression: Understandings on the Neurobiological Etiology that Lead to Novel Pharmacological Treatment Options

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.

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Pharmacological Treatments for Patients with Treatment-Resistant Depression

Pharmaceuticals ◽

10.3390/ph13060116 ◽

2020 ◽

Vol 13 (6) ◽

pp. 116 ◽

Cited By ~ 2

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.

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

BJPsych Bulletin ◽

10.1192/bjb.2021.105 ◽

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.

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

Current Pharmaceutical Design ◽

10.2174/1381612826666200110101604 ◽

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.

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

European Psychiatry ◽

10.1192/j.eurpsy.2020.3 ◽

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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Critical review of available treatment options for treatment refractory depression and anxiety - clinical and ethical dilemmas

Medicinski pregled ◽

10.2298/mpns1606171k ◽

2016 ◽

Vol 69 (5-6) ◽

pp. 171-176 ◽

Cited By ~ 2

Author(s):

Dusan Kolar ◽

Michael Kolar

Keyword(s):

Anxiety Disorders ◽

Ethical Dilemmas ◽

Treatment Options ◽

Depression And Anxiety ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Symptoms Of Depression ◽

Mood And Anxiety Disorders ◽

Resistant Depression ◽

Treatment Refractory

Treatment-resistant mood and anxiety disorders require an intensive therapeutic approach, and it should balance benefits and adverse effects or other potential detrimental effects of medications. The goal of treatment is to provide consistent and lasting improvement in symptoms of depression and anxiety. Benzodiazepines are effective for anxiety symptoms, but with no sustained treatment effects. Other medication treatment options for anxiety disorders are outlined. Ketamine is usually very effective in treating major depressive disorder but without sustained benefits. Long-term use may pose a significant risk of developing tolerance and dependence. Stimulant medication augmentation for treatment-resistant depression is effective for residual symptoms of depression, but effects are usually short-lasting and it sounds more as an artificial way of improving energy, alertness and cognitive functioning. Synthetic cannabinoids and medical marijuana are increasingly prescribed for various medical conditions, but more recently also for patients with mood and anxiety disorders. All of these treatments may raise ethical dilemmas about appropri?ateness of prescribing these medications and a number of questions regarding the optimal treatment for patients with treatment-resistant depression and treatment refractory anxiety disorders.

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

Acta Neuropsychiatrica ◽

10.1017/neu.2019.25 ◽

2019 ◽

Vol 31 (05) ◽

pp. 258-265 ◽

Cited By ~ 3

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.

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Emerging therapies for treatment resistant depression

Mental Health Clinician ◽

10.9740/mhc.n207179 ◽

2014 ◽

Vol 4 (5) ◽

pp. 226-230 ◽

Cited By ~ 2

Author(s):

Ruki Wijesinghe

Keyword(s):

Treatment Options ◽

Nmda Antagonist ◽

Brain Regions ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Significant Drop ◽

Magnetic Seizure Therapy ◽

New Strategy ◽

Resistant Depression ◽

New Research

Despite new insights and evidence-based treatment options for clinical depression in the recent years, the current choices of safe and effective therapies are still inadequate to sustain a long-term response in the depressed patient. Many do not improve, improve partially or are classified as ‘treatment resistant’ with poor compliance and marked functional impairment. The aim of this article is to review future therapeutic options and advances in treatments available for this cohort of patients. Several innovative and promising studies are underway to explore the role of ketamine, a glutamate N-methyl-d-aspartate (NMDA) antagonist in treating treatment-resistant depression and acute suicidal ideation. Furthermore, new research reveals that depression is associated with a significant drop in neurotrophic factors such as brain derived neurotrophic factor (BDNF) and increasing BDNF may be a new strategy for developing new antidepressants. Neuromodulation interventions by stimulating specific brain regions including deep brain stimulation (DBS), magnetic seizure therapy (MST), and transcranial direct current stimulation (tDCS), still in experimental stages, are also discussed.

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Efficacy and acceptability of adjunctive psychological and pharmacological interventions for treatment-resistant depression: protocol for a systematic review and network meta-analysis

BMJ Open ◽

10.1136/bmjopen-2018-028538 ◽

2019 ◽

Vol 9 (5) ◽

pp. e028538 ◽

Cited By ~ 1

Author(s):

Muhammad Ishrat Husain ◽

Rebecca Strawbridge ◽

Ben Carter ◽

Brett D M Jones ◽

Allan Young ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Treatment Options ◽

Treatment Modalities ◽

Evidence Based ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Academic Journal ◽

Resistant Depression ◽

Randomised Controlled

IntroductionMajor depressive disorder (MDD) is a common debilitating illness worldwide. The vast majority of patients with MDD will not achieve remission with first-line treatment and despite the availability of different treatment modalities, at least one-third of patients experience treatment-resistant depression (TRD). There continues to be a paucity of research focused on treatment options for patients with TRD thus treatment decisions are largely based on patient and clinician preference as opposed to evidence-based practice. Herein we propose a systematic review and network meta-analysis (NMA) of available pharmacological and psychological augmentation treatments for TRD, to inform evidence-based management of TRD.Methods and analysisWe plan to conduct a search of electronic databases (MEDLINE and ISIWEB) of all dates from inception for randomised controlled trials of pharmacological and psychological augmentation interventions for adults with TRD. Articles for review will be included based upon consensus from two authors. Pharmaceutical companies will be contacted for access to any unpublished data. An NMA will compare the effectiveness pharmacological adjunctive agents for TRD using preanalysis/postanalysis, assuming consistency and transitivity.Ethics and disseminationThis project does not require research ethics board approval. The dissemination plan is to present findings at international scientific meetings and publishing results in a peer-reviewed academic journal.PROSPERO registration numberCRD42019132588.

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Remission of treatment-resistant depression with tardive akathisia with electroconvulsive therapy

BMJ Case Reports ◽

10.1136/bcr-2019-229714 ◽

2019 ◽

Vol 12 (9) ◽

pp. e229714 ◽

Cited By ~ 2

Author(s):

Thanos Emmanuel

Keyword(s):

Electroconvulsive Therapy ◽

Treatment Options ◽

Treatment Intervention ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Drug Induced ◽

Resistant Depression ◽

New Situation ◽

Tardive Akathisia

This report presents a case of drug-induced severe tardive akathisia developing after the combination of a selective serotonin reuptake inhibitor and an antipsychotic, in a woman with severe major depression. The trial and combination of multiple medications is common practice in treatment-resistant patients with depression. With the increase in the prevalence of treatment-resistant depression, adverse effects of medication such as tardive akathisia are becoming more common. Tardive akathisia persists even after the withdrawal of the causative agent and is very challenging to treat. The patient did not respond to any standard medications indicated for drug-induced akathisia. As a result, the patient became suicidal and extremely distressed with all treatment options exhausted. Guidelines on the management of drug-induced tardive akathisia are non-existent. This reflects the importance of this case study, which reveals the complete remission of both tardive akathisia and all the patient’s depressive symptoms after electroconvulsive therapy . This report provides evidence of an established treatment intervention used in a new situation.

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