Treatment-resistant depression: therapeutic trends, challenges, and future directions

Al-harbi

doi:10.2147/ppa.s29716

Cited by 796Treatment of Major DepressionElectroconvulsive Therapy StudiesTranscranial Magnetic Stimulation Studies

Treatment-resistant depression: therapeutic trends, challenges, and future directions

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Al-harbi·2012·Patient Preference and Adherence

DOI 10.2147/ppa.s29716PMC PMC3363299

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Abstract

BACKGROUND: Patients with major depression respond to antidepressant treatment, but 10%-30% of them do not improve or show a partial response coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. The aim of this paper is to review the therapeutic options for treating resistant major depressive disorder, as well as evaluating further therapeutic options. METHODS: In addition to Google Scholar and Quertle searches, a PubMed search using key words was conducted, and relevant articles published in English peer-reviewed journals (1990-2011) were retrieved. Only those papers that directly addressed treatment options for treatment-resistant depression were retained for extensive review. RESULTS: Treatment-resistant depression, a complex clinical problem caused by multiple risk factors, is targeted by integrated therapeutic strategies, which include optimization of medications, a combination of antidepressants, switching of antidepressants, and augmentation with non-antidepressants, psychosocial and cultural therapies, and somatic therapies including electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As a corollary, more than a third of patients with treatment-resistant depression tend to achieve remission and the rest continue to suffer from residual symptoms. The latter group of patients needs further study to identify the most effective therapeutic modalities. Newer biomarker-based antidepressants and other drugs, together with non-drug strategies, are on the horizon to address further the multiple complex issues of treatment-resistant depression. CONCLUSION: Treatment-resistant depression continues to challenge mental health care providers, and further relevant research involving newer drugs is warranted to improve the quality of life of patients with the disorder.

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Between one-half and two-thirds of people with depressive disorder do not reach a response threshold with antidepressants.
“A significant proportion of depressed people, ranging between one-half and two-thirds, do not reach a response threshold (Al-Harbi 2012; Trivedi 2006).”
From Psychotherapeutic treatments for depression in older adults (2024) · cites this paper as Al-Harbi 2012
The Introduction says 60%–70% of patients with depression respond to antidepressant therapy, implying 30%–40% do not respond—not one-half to two-thirds. Its 50%–66% figure refers instead to patients who do not recover fully on an antidepressant, a different outcome from failing to reach a response threshold. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
10% to 30% of depression patients do not respond to antidepressant medication.
“It has been estimated that 10% to 30% of depression patients do not respond to antidepressant medication,32”
From Study protocol on the efficacy of exergames-acceptance and commitment therapy program for the treatment of major depressive disorder: Comparison with acceptance and commitment therapy alone and treatment-as-usual in a multicentre randomised controlled trial (2024) · cites this paper as [32]
More than a third of patients with major depressive disorder fail to achieve remission even after several rounds of treatment.
“while more than a third fail to achieve remission even after several rounds of treatment ( Al-Harbi, 2012 , Gaynes et al., 2009 , Strawbridge et al., 2022 )”
From Self-blame-selective hyper-connectivity between anterior temporal and subgenual cortices predicts prognosis in major depressive disorder (2023) · cites this paper as Al-Harbi, 2012

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Pathak, L., Agrawal, Y. K., & Dhir, A. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.794783 · Cited by 142 · see citing works
Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression
Hamer, J., Testani, D. A., Mansur, R. B., Lee, Y. L., Subramaniapillai, M., & McIntyre, R. S. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.01.016 · Cited by 139 · see citing works
Psilocybin-assisted therapy for depression: A systematic review and meta-analysis
Haikazian, S., Chen-Li, D. C. J., Johnson, D. E., Fancy, F., Levinta, A., Husain, M. I., Mansur, R. B., McIntyre, R. S., & Rosenblat, J. D. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115531 · Cited by 134 · see citing works
Brain-spleen axis in health and diseases: A review and future perspective
Wei, Y., Wang, T., Liao, L., Fan, X., Chang, L., & Hashimoto, K. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.02.008 · Cited by 134 · see citing works
“Antidepressants have numerous clinical treatment challenges, given that approximately 30%–40% of patients with depression do not respond to traditional antidepressants and risk of recurrence is almost 40% after initial therapy (Al-Harbi, 2012; Kato et al., 2021).”
A brief history of antidepressant drug development: from tricyclics to beyond ketamine
Pereira, V. S., & Sato, V. (2018) · Acta Neuropsychiatrica · doi:10.1017/neu.2017.39 · Cited by 129 · see citing works
“According to some authors, this number ranges from 30% (49) to 45% of the patients (50), whereas the literature comprises many different assumptions.”
Effects of ginseng on stress-related depression, anxiety, and the hypothalamic–pituitary–adrenal axis
Lee, S., & Rhee, D. (2017) · Journal of Ginseng Research · doi:10.1016/j.jgr.2017.01.010 · Cited by 132 · see citing works
The role of neuroinflammation on pathogenesis of affective disorders
Rhie, S. J., Jung, E.-Y., & Shim, I. (2020) · Journal of Exercise Rehabilitation · doi:10.12965/jer.2040016.008 · Cited by 126 · see citing works
The Role of the Oral Microbiota Related to Periodontal Diseases in Anxiety, Mood and Trauma- and Stress-Related Disorders
Martínez, M., Postolache, T. T., García‐Bueno, B., Leza, J. C., Figuero, E., Lowry, C. A., & Malan‐Müller, S. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.814177 · Cited by 127 · see citing works
“Adherence to psychiatric medications is further hindered by their side-effect profiles (5), and, due to the limited efficacy of antidepressants, nearly a third of patients do not respond to treatment (6).”
Background
5-HT3 Receptor Antagonism: A Potential Therapeutic Approach for the Treatment of Depression and other Disorders
Bhatt, S., Devadoss, T., Manjula, S. N., & Rajangam, J. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666201015155816 · Cited by 119 · see citing works
Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review
Mura, G., Moro, M., Patten, S., & Carta, M. (2014) · CNS Spectrums · doi:10.1017/s1092852913000953 · Cited by 113 · see citing works
Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states
González-Arias, C., Sánchez-Ruiz, A., Esparza, J., Sánchez‐Puelles, C., Arancibia, L., Ramírez‐Franco, J., Gobbo, D., Kirchhoff, F., & Perea, G. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02269-8 · Cited by 122 · see citing works
“The currently available treatments are only effective in half of MDD patients, revealing the complex heterogeneous nature of the disorder, which possibly involves multiple etiologies [42].”
Background
Mental Health Care in Saudi Arabia: Past, Present and Future
Koenig, H. G., Zaben, F. A., Sehlo, M. G., Khalifa, D. A., Ahwal, M. S. A., Qureshi, N. A., & Alhabeeb, A. A. (2014) · Open Journal of Psychiatry · doi:10.4236/ojpsych.2014.42016 · Cited by 111 · see citing works
“Mental health research in treatment resistent depression has been a particular interest of Saudi researchers in recent years [77] [78].”
Background
Alleviation of depression by glucagon-like peptide 1 through the regulation of Neuroinflammation, neurotransmitters, neurogenesis, and synaptic function
Kim, Y.-K., Kim, O. Y., & Song, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01270 · Cited by 109 · see citing works
“Although numerous anti-depressive treatments are available, 30% of patients diagnosed with depression do not experience positive therapeutic effects with these therapies (Al-Harbi, 2012).”
Background
HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress
Zhong, P., Vickstrom, C. R., Liu, X., Hu, Y., Yu, L., Yu, H.-G., & Liu, Q.-S. (2018) · eLife · doi:10.7554/elife.32420 · Cited by 99 · see citing works
Repetitive transcranial magnetic stimulation for stroke rehabilitation: insights into the molecular and cellular mechanisms of neuroinflammation
Sheng, R., Chen, C., Chen, H., & Yu, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1197422 · Cited by 108 · see citing works
Ketamine for depression
Jelen, L. A., & Stone, J. M. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2020.1854194 · Cited by 102 · see citing works
“Firstly, there is a significant delay in the onset of therapeutic action (from weeks to months) and secondly, up to a third of patients fail to demonstrate an adequate response, with many developing persistent, treatment-resistant depression (TRD) (Al-Harbi, 2012).”
Background
The opioid system in depression
Jelen, L. A., Stone, J. M., Young, A. H., & Mehta, M. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104800 · Cited by 102 · see citing works
“In healthy subjects, esmethadone has been found to increase circulating levels of brain-derived neurotrophic factor (BDNF) (De Martin et al., 2021), a neurotrophin widely expressed in the central nervous system that exhibits important effects on neural plasticity, and in a recent phase II placebo-controlled, randomise…”
Influential
Deep brain stimulation for psychiatric disorders: where we are now
Cleary, D. R., Ozpinar, A., Raslan, A. M. T., & Ko, A. L. (2015) · Neurosurgical FOCUS · doi:10.3171/2015.3.focus1546 · Cited by 99 · see citing works
Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential?
Kočárová, R., Horáček, J., & Carhart-Harris, R. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.661233 · Cited by 96 · see citing works
Deep transcranial magnetic stimulation (dTMS)—Beyond depression
Tendler, A., Barnea Ygael, N., Roth, Y., & Zangen, A. (2016) · Expert Review of Medical Devices · doi:10.1080/17434440.2016.1233812 · Cited by 93 · see citing works
“ity of psychotherapy and over four classes and 30 distinct pharmacologic agents, a large portion (32–52%) of the MDD population are still considered treatment resistant [8,9].”
Background
Cortical Connectivity Moderators of Antidepressant vs Placebo Treatment Response in Major Depressive Disorder
Rolle, C. E., Fonzo, G. A., Wu, W., Toll, R. T., Jha, M. K., Cooper, C. M., Fatt, C. C., Pizzagalli, D. A., Trombello, J. M., Deckersbach, T., et al. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2019.3867 · Cited by 90 · see citing works
Repetitive transcranial magnetic stimulation in patients with drug-resistant major depression: A six-month clinical follow-up study
Concerto, C., Lanza, G., Cantone, M., Ferri, R., Pennisi, G., Bella, R., & Aguglia, E. (2015) · International journal of psychiatry in clinical practice · doi:10.3109/13651501.2015.1084329 · Cited by 89 · see citing works
Pharmacologic approaches to treatment resistant depression: Evidences and personal experience
Tundo, A., de Filippis, R., & Proietti, L. (2015) · World Journal of Psychiatry · doi:10.5498/wjp.v5.i3.330 · Cited by 91 · see citing works
Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion
Chen, M.-H., Li, C.-T., Lin, W.-C., Hong, C.-J., Tu, P.-C., Bai, Y.-M., Cheng, C.-M., & Su, T.-P. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.07.033 · Cited by 86 · see citing works
Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets
Misiak, B., Beszłej, J. A., Kotowicz, K., Szewczuk-Bogusławska, M., Samochowiec, J., Kucharska–Mazur, J., & Frydecka, D. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.04.021 · Cited by 86 · see citing works
“In addition, it has been estimated that up to 30% of patients with MDD do not improve during antidepressant treatment or respond partially, presenting with functional impairment, poor quality of life, suicidal ideation, self-injurious behaviour and a high relapse rate (Al-Harbi, 2012).”
Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: Basic science, evidence-based knowledge and expert guidance
Kasper, S. F., Cubała, W. J., Fagiolini, A. M., Ramos‐Quiroga, J. A., Souery, D., & Young, A. H. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2020.1836399 · Cited by 86 · see citing works
Modeling psychiatric disorders with patient-derived iPSCs
Wen, Z., Christian, K. M., Song, H., & Ming, G.-L. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.11.003 · Cited by 84 · see citing works
“Currently available drugs are primarily targeted at relieving symptoms, are often only partially effective, and have significant side effects on wellfunctioning neural systems [3,4].”
Background
Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo–control study
Chen, M.-H., Cheng, C.-M., Gueorguieva, R., Lin, W.-C., Li, C.-T., Hong, C.-J., Tu, P.-C., Bai, Y.-M., Tsai, S.-J., Krystal, J. H., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0480-y · Cited by 84 · see citing works
Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice
Falcón, E., Maier, K. L., Robinson, S. A., Hill‐Smith, T. E., & Lucki, I. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3723-y · Cited by 85 · see citing works
“In fact, approximately 30 % of patients suffer from treatment-resistant depression (TRD), where they do not respond to at least two antidepressant medications (Al-Harbi 2012).”
Behavioral and Neurobiological Effects of Deep Brain Stimulation in a Mouse Model of High Anxiety- and Depression-Like Behavior
Schmuckermair, C., Gaburro, S., Sah, A., Landgraf, R., Sartori, S. B., & Singewald, N. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.21 · Cited by 81 · see citing works
Understanding exosomes: Part 2-Emerging leaders in regenerative medicine.
Miron, R., Estrin, N., Sculean, A., & Zhang, Y.-F. (2024) · Periodontology 2000 · doi:10.1111/prd.12561 · Cited by 89 · see citing works
Finding factors that predict treatment-resistant depression: results of a cohort study
Cepeda, M. S., Reps, J., & Ryan, P. (2018) · Depression and Anxiety · doi:10.1002/da.22774 · Cited by 80 · see citing works
“Anxiety disorders are common in subjects with depression (Wu, Erickson, Piette, & Balkrishnan, 2012), and have been identified as a risk factor for not responding well to treatment (Al-Harbi, 2012; Bennabi et al., 2015; Souery et al., 2007; van Looet al., 2014).”
Background
Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice
Ma, L., Ni, L., Yang, T., Mao, P., Huang, X. H., Luo, Y., Jiang, Z., Hu, L., Zhao, Y., Fu, Z., et al. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c07095 · Cited by 82 · see citing works
Meaningful Change in Depression Symptoms Assessed with the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) Among Patients with Treatment Resistant Depression in Two, Randomized, Double-blind, Active-controlled Trials of Esketamine Nasal Spray Combined With a New Oral Antidepressant
Hudgens, S. A., Floden, L. L., Blackowicz, M. J., Jamieson, C., Popova, V., Fedgchin, M. M., Drevets, W. C., Cooper, K., Lane, R., & Singh, J. B. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.066 · Cited by 80 · see citing works
Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study
Chen, M.-H., Lin, W.-C., Tu, P.-C., Li, C.-T., Bai, Y.-M., Tsai, S.-J., & Su, T.-P. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.08.022 · Cited by 78 · see citing works
On ‘polypharmacy’ and multi-target agents, complementary strategies for improving the treatment of depression: a comparative appraisal
Millan, M. J. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712001496 · Cited by 78 · see citing works
Role of Brain-Gut-Microbiota Axis in Depression: Emerging Therapeutic Avenues
Bhatt, S., Kanoujia, J., Lakshmi, S. M., Patil, C., Gupta, G., Chellappan, D. K., & Dua, K. (2022) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527321666220329140804 · Cited by 81 · see citing works
More Realistic Forecasting of Future Life Events After Psilocybin for Treatment-Resistant Depression
Lyons, T., & Carhart-Harris, R. L. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.01721 · Cited by 77 · see citing works
“Approximately 30% of MDD patients suffer from treatmentresistant depression (TRD) (Gaynes, 2009; Al-Harbi, 2012) and much of the burden associated with MDD can be accounted for by treatment resistance (Greden, 2001).”
Background
Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress.
Dionisie, V., Ciobanu, A. M., Toma, V. A., Manea, M. C., Baldea, I., Olteanu, D., Sevastre-Berghian, A., Clichici, S., Manea, M., Riga, S., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147483 · Cited by 78 · see citing works
Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges
Visentin, A. P. V., Colombo, R., Scotton, E., Fracasso, D. S., Rosa, A. R., Branco, C. S., & Salvador, M. M. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2972968 · Cited by 77 · see citing works
“remission upon receiving antidepressant treatment, and treatment response rates appear to drop with each subsequent retry [3, 4].”
Background
Real-world evidence from a European cohort study of patients with treatment resistant depression: Treatment patterns and clinical outcomes
Heerlein, K., Perugi, G., Otte, C., Frodl, T., Degraeve, G., Hagedoorn, W., Oliveira-Maia, A. J., Pérez, V., Rathod, S., Rosso, G., et al. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.03.073 · Cited by 76 · see citing works
Neuroimmunology of depression
Sarno, E., Moeser, A. J., & Robison, A. J. (2021) · Advances in pharmacology · doi:10.1016/bs.apha.2021.03.004 · Cited by 80 · see citing works
“Moreover, the most effective treatments also vary by individual, and about 10–30% of patients do not improve or show partial improvement with current treatments (Al-Harbi, 2012).”
Background
Investigational drugs in recent clinical trials for treatment-resistant depression
Garay, R. P., Zarate, C. A., Charpeaud, T., Citrome, L., Correll, C. U., Hameg, A., & Llorca, P. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2017.1283217 · Cited by 74 · see citing works
Kynurenic acid is a potential overlapped biomarker between diagnosis and treatment response for depression from metabolome analysis
Erabi, H., Okada, G., Shibasaki, C., Setoyama, D., Kang, D., Takamura, M., Yoshino, A., Fuchikami, M., Kurata, A., Kato, T. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73918-z · Cited by 73 · see citing works
Clinical applications of EEG power spectra aperiodic component analysis: A mini-review
Pani, S. M., Saba, L., & Fraschini, M. (2022) · Clinical Neurophysiology · doi:10.1016/j.clinph.2022.08.010 · Cited by 74 · see citing works
“A large portion of patients recover, often not permanently, but there is also a part of them that is treatment-resistant (Al-Harbi, 2012).”
Background
Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder
Ragguett, R., Rong, C., Rosenblat, J. D., Ho, R., & McIntyre, R. S. (2018) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2018.1459564 · Cited by 72 · see citing works
Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review
Salahudeen, M. S., Wright, C. M., & Peterson, G. M. (2020) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098620937899 · Cited by 72 · see citing works
Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder
Pae, C., Wang, S., Han, C., Lee, S.-J., Patkar, A. A., Masand, P. S., & Serretti, A. (2015) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.140120 · Cited by 71 · see citing works
Bacterial Extracellular Vesicles and the Gut‐Microbiota Brain Axis: Emerging Roles in Communication and Potential as Therapeutics
Pirolli, N. H., Bentley, W. E., & Jay, S. M. (2021) · Advanced Biology · doi:10.1002/adbi.202000540 · Cited by 70 · see citing works
Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine
Chen, B. K., Luna, V. M., LaGamma, C. T., Xu, X., Deng, S., Suckow, R. F., Cooper, T. B., Shah, A., Brachman, R. A., Mendez‐David, I., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0714-z · Cited by 68 · see citing works
Neuroinflammation at the interface of depression and cardiovascular disease: Evidence from rodent models of social stress
Finnell, J. E., & Wood, S. K. (2016) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.04.001 · Cited by 68 · see citing works
“Approximately 10e30% of those suffering from depression exhibit treatment resistance (Al-Harbi, 2012), which has been linked to an increase in circulating cytokines (Maes et al., 1997; Musselman et al., 2001b; Miller et al., 2002; Alesci et al., 2005; Motivala et al., 2005; Raison et al., 2013).”
Prebiotics modulate the microbiota-gut-brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice.
de Paiva, I. H. R., Maciel, L. M., da Silva, R. S., Mendonça, I. P., de Souza, J. D., & Peixoto, C. A. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114153 · Cited by 70 · see citing works
Humanistic outcomes in treatment resistant depression: a secondary analysis of the STAR*D study
DiBernardo, A., Lin, X., Zhang, Q., Xiang, J., Lu, L., Jamieson, C., Benson, C., Lee, K., Bodén, R., Brandt, L., et al. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1920-7 · Cited by 66 · see citing works
Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study
Savitz, A. J., Wajs, E., Zhang, Y., Xu, H., Etropolski, M. S., Thase, M. E., & Drevets, W. C. (2021) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab050 · Cited by 66 · see citing works
Is Off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications
Zhang, M. W., Harris, K. M., & Ho, R. (2016) · BMC Medical Ethics · doi:10.1186/s12910-016-0087-3 · Cited by 65 · see citing works
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
de Miranda, A. S., de Barros, J. L. V. M., & Teixeira, A. L. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1846720 · Cited by 64 · see citing works
The molecular aspects of oxidative & nitrosative stress and the tryptophan catabolites pathway (TRYCATs) as potential causes of depression
Wigner, P., Czarny, P. L., Gałecki, P., Su, K., & Śliwiński, T. (2017) · Psychiatry Research · doi:10.1016/j.psychres.2017.09.045 · Cited by 64 · see citing works
GluN2A mediates ketamine-induced rapid antidepressant-like responses
Su, T., Lu, Y., Fu, C., Geng, Y., & Chen, Y. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01436-y · Cited by 63 · see citing works
Plant-based dietary quality and depressive symptoms in Australian vegans and vegetarians: a cross-sectional study
Lee, M. F., Eather, R., & Best, T. (2021) · BMJ Nutrition Prevention & Health · doi:10.1136/bmjnph-2021-000332 · Cited by 65 · see citing works
Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders
Liu, J., Cheng, Y., Li, M., Zhang, Z., Li, T., & Luo, X. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01456-5 · Cited by 59 · see citing works
Comparative study of esketamine and racemic ketamine in treatment-resistant depression
Correia‐Melo, F. S., Leal, G. C.-G., Carvalho, M. S., Jesus‐Nunes, A. P., Ferreira, C. B., Vieira, F., Magnavita, G. M., Vale, L. A. S., Mello, R. P., Nakahira, C., et al. (2018) · Medicine · doi:10.1097/md.0000000000012414 · Cited by 61 · see citing works
“This issue reinforces the urgent need for new therapies to manage treatment-resistant depression (TRD).([2]) Several clinical studies have shown that ketamine, an anesthetic drug with dissociative properties, provides a surprisingly rapid and robust antidepressant effect, when used in subanesthetic doses.”
Background
Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel
Maina, G., Adami, M., Ascione, G., Bondi, E., Berardis, D. D., Delmonte, D., Maffezzoli, S., Martinotti, G., Nivoli, A., Ottavianelli, E., et al. (2023) · Annals of General Psychiatry · doi:10.1186/s12991-023-00478-7 · Cited by 59 · see citing works
Gastrodin ameliorates depression-like behaviors and up-regulates proliferation of hippocampal-derived neural stem cells in rats: Involvement of its anti-inflammatory action
Wang, H., Zhang, R., Qiao, Y., Xue, F., Nie, H., Zhang, Z., Wang, Y., Peng, Z., & Tan, Q. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.02.046 · Cited by 57 · see citing works
The Potential of Polygenic Risk Scores to Predict Antidepressant Treatment Response in Major Depression: A Systematic Review
Meerman, J. J., ter Hark, S. E., Janzing, J., & Coenen, M. J. H. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.02.015 · Cited by 58 · see citing works
Differential Gut Microbiota Compositions Related With the Severity of Major Depressive Disorder
Zhong, Q., Chen, J., Wang, Y., Shao, W., Zhou, C., & Xie, P. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.907239 · Cited by 57 · see citing works
Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications
Timberlake, M. A., & Dwivedi, Y. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0241-z · Cited by 57 · see citing works
Profiling changes in cortical astroglial cells following chronic stress
Simard, S., Coppola, G., Rudyk, C., Hayley, S. P., McQuaid, R. J., & Salmaso, N. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0105-x · Cited by 58 · see citing works
“Currently, treatments for depression include psychotherapy, antidepressant medications, and in some extreme cases, electroconvulsive therapy; however, an estimated 30–40% of individuals are treatment resistant [2].”
Background
Sex Differences in the Behavioral, Molecular, and Structural Effects of Ketamine Treatment in Depression
Ponton, E., Turecki, G., & Nagy, C. (2021) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab082 · Cited by 58 · see citing works
“…which take multiple weeks to show therapeutic effects and only 30%–40% of people respond to the first line of therapeutics (Nierenberg et al., 2000; Lieberman et al., 2008; Machado-Vieira 76 | International Journal of Neuropsychopharmacology, 2022 et al., 2010; Al-Harbi 2012; Kato et al., 2018).”
The economics of psychedelic-assisted therapies: A research agenda
Marseille, E. A., Bertozzi, S., & Kahn, J. G. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1025726 · Cited by 56 · see citing works
Ketamine and Esketamine in Clinical Trials: FDA‐ Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations
Vekhova, K. A., Namiot, E. D., Jonsson, J., & Schiöth, H. B. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3478 · Cited by 58 · see citing works
Technical and clinical considerations for electroencephalography-based biomarkers for major depressive disorder
Simmatis, L. E. R., Russo, E. E., Geraci, J., Harmsen, I. E., & Samuel, N. (2023) · npj Mental Health Research · doi:10.1038/s44184-023-00038-7 · Cited by 52 · see citing works
“Although several classes of pharmacological treatments for MDD exist, only 60 – 70% of patients respond adequately to two trials of different classes of antidepressants, after which patients are considered to have treatment-resistant depression 43 .”
Transcranial Direct Current Stimulation and Cognitive-Behavioral Therapy: Evidence of a Synergistic Effect in Treatment-Resistant Depression
D’Urso, G., Mantovani, A., Micillo, M., Priori, A., & Muscettola, G. (2012) · Brain stimulation · doi:10.1016/j.brs.2012.09.003 · Cited by 52 · see citing works
Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant
Xu, S., Yao, X., Li, B., Cui, R., Zhu, C., Wang, Y., & Yang, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.740996 · Cited by 51 · see citing works
“Such shortcomings of traditional antidepressants have hindered their application to patients with resistance to standard treatment or with suicidal ideation which demands immediate intervention (Al-Harbi, 2012; Rincon-Cortes and Grace, 2020).”
Background
A Randomized, Double-Blind, Midazolam-Controlled Trial of Low-Dose Ketamine Infusion in Patients With Treatment-Resistant Depression and Prominent Suicidal Ideation
Su, T., Li, C., Lin, W., Wu, H.-J., Tsai, S., Bai, Y., Mao, W., Tu, P., Chen, L., Li, W., et al. (2023) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyad014 · Cited by 56 · see citing works
“In a real-world clinical setting, however, TRD and severe suicidal ideation commonly occur together and exacerbate the effects of one another (Montgomery, 1980; Al-Harbi, 2012).”
Background
NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA
Song, N., Liu, Z., Gao, Y., Lu, S., Yang, S., & Yuan, C. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02476-x · Cited by 50 · see citing works
“A significant number of patients with major depressive disorder (MDD) remain inadequately treated and display nonresponse or partial response after all treatment options have been explored [2, 3].”
The MAKE Biomarker Discovery for Enhancing anTidepressant Treatment Effect and Response Study: Design and Methodology
Kang, H., Kim, J., Kim, S. Y., Kim, S., Shin, H., Shin, M., & Kim, J. (2018) · Psychiatry Investigation · doi:10.30773/pi.2017.10.2 · Cited by 50 · see citing works
Inflammatory Pathways in Psychiatric Disorders: the Case of Schizophrenia and Depression
Feng, T., Tripathi, A., & Pillai, A. (2020) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-020-00207-4 · Cited by 50 · see citing works
Estimating Prevalence and Healthcare Utilization for Treatment-Resistant Depression in Japan: A Retrospective Claims Database Study
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Zinc in depression: From development to treatment: A comparative/ dose response meta-analysis of observational studies and randomized controlled trials
Yosaee, S., Clark, C. C. T., Keshtkaran, Z., Ashourpour, M., Keshani, P., & Soltani, S. (2020) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2020.08.001 · Cited by 48 · see citing works

Authors: Al-harbi
Venue: Patient Preference and Adherence
Publisher: Informa UK Limited
Published: 2012-05
Volume: 6
Pages: 369
ISSN: 1177-889X (ISSN-L)
DOI: 10.2147/ppa.s29716
PMC: PMC3363299
OpenAlex: W2016292245
Cited by: 796
References: 155
Citations by year: 2026: 75 · 2025: 76 · 2024: 104 · 2023: 95 · 2022: 107 · 2021: 91 · 2020: 63 · 2019: 56 · 2018: 38 · 2017: 33 · 2016: 18 · 2015: 15 · 2014: 14 · 2013: 6 · 2012: 3
FWCI: 8.94
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/3.0/ (vor)
Locations: Patient Preference and Adherence (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders: King Saud bin Abdulaziz University for Health Science
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords: treatment-resistant depression, major depressive disorder, antidepressant augmentation, antidepressant switching, antidepressant combination therapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, transcranial direct current stimulation, magnetic seizure therapy, psychosocial interventions, relapse

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Treatment-resistant depression: therapeutic trends, challenges, and future directions

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