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

The DOI matches its Crossref record; 151 of the 155 references it cites were found in a registry or an index.

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

Open access

Al-harbi·2012·Patient Preference and Adherence

Open this paper in CoChat — free account Open PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.2147/ppa.s29716

Cites

151 of 151 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The serotonin syndrome
Sternbach, H. A. (1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.6.705 · Cited by 1,349
Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders
Sanacora, G., Zarate, C. A., Krystal, J. H., & Manji, H. K. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2462 · Cited by 894
DEFINITION AND EPIDEMIOLOGY OF TREATMENT-RESISTANT DEPRESSION
Fava, M., & Davidson, K. G. (1996) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(05)70283-5 · Cited by 797
Untitled work
(2001) · PubMed · Cited by 780
Untitled work
(1997) · PubMed · Cited by 727
Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression
Brent, D. A., Emslie, G. J., Clarke, G. N., Wagner, K. D., Asarnow, J. R., Keller, M., Vitiello, B., Ritz, L., Iyengar, S., Abebe, K. Z., et al. (2008) · JAMA · doi:10.1001/jama.299.8.901 · Cited by 713
Tryptophan Hydroxylase-2 Controls Brain Serotonin Synthesis
Zhang, X., Beaulieu, J., Sotnikova, T. D., Gainetdinov, R. R., & Caron, M. G. (2004) · Science · doi:10.1126/science.1097540 · Cited by 683
Suicide attempts and nonsuicidal self-injury in the treatment of resistant depression in adolescents: findings from the TORDIA study
Asarnow, J. R., Porta, G., Spirito, A., Emslie, G., Clarke, G., Wagner, K. D., Vitiello, B., Keller, M., Birmaher, B., McCracken, J., et al. (2011) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2011.04.003 · Cited by 632
Comorbid depression and anxiety spectrum disorders
Gorman, J. M. (1996) · Depression and Anxiety · doi:10.1002/(sici)1520-6394(1996)4:4 · Cited by 629
Vagus nerve stimulation (VNS™) for treatment-resistant depression: efficacy, side effects, and predictors of outcome
Sackeim, H. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00271-8 · Cited by 568

Flagged first, then by citations

Show all 155 references

4 of the 155 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

[5]American Psychiatric Association Practice Guideline for the Treatment of Patients with Major Depression 2000 Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision Washington, DC American Psychiatric Association 2000
[37]Phillips KA Nierenberg AA The assessment and treatment of refractory depression J Clin Psychiatry 1994 55 20 26 8077165
[82]Nemeroff CB Use of atypical antipsychotics in refractory depression and anxiety J Clin Psychiatry 2005 66 Suppl 8 13 21 16336032
[110]Torres CV Lozano AM Deep brain stimulation in the treatment of therapy-refractory depression Rev Neurol 2008 47 477 482 18985598

Sorted by citations

Dendritic structural plasticity and neuropsychiatric disease
Forrest, M. P., Parnell, E., & Penzes, P. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.16 · Cited by 464
Treatment-resistant depression and peripheral C-reactive protein.
Chamberlain, S. R., Cavanagh, J., de Boer, P., Mondelli, V., Jones, D. N. C., Drevets, W. C., Cowen, P. J., Harrison, N. A., Pointon, L., Pariante, C. M., et al. (2019) · British Journal of Psychiatry · doi:10.1192/bjp.2018.66 · Cited by 400
“45,46 Because of the global burden of disability attributable to MDD, 47 the search for improved understanding of biomarkers of therapeutic resistance to current first-line treatment options is pressing.”
Neural basis of major depressive disorder: Beyond monoamine hypothesis
Boku, S., Nakagawa, S., Toda, H., & Hishimoto, A. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12604 · Cited by 402
Gut microbial metabolites in depression: understanding the biochemical mechanisms
Caspani, G., Kennedy, S. H., Foster, J. A., & Swann, J. R. (2019) · Microbial Cell · doi:10.15698/mic2019.10.693 · Cited by 289
Gut feelings: a randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms
Chahwan, B., Kwan, S., Isik, A., van Hemert, S., Burke, C., & Roberts, L. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.04.097 · Cited by 256
“Research indicates that these treatments are effective in reducing depressive symptoms, with approximately 60–70% of patients responding to treatment (Al-Harbi, 2012).”
Background
Ketamine: A tale of two enantiomers
Jelen, L. A., Young, A. H., & Stone, J. M. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120959644 · Cited by 266
“These include a significant delay in the onset of therapeutic action (weeks to months) and approximately one-third of patients with major depressive disorder (MDD) failing to demonstrate an adequate response (Al-Harbi, 2012).”
Background
Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial
Schaub, A.-C., Schneider, E., Vázquez-Castellanos, J. F., Schweinfurth, N., Kettelhack, C., Doll, J. P. K., Yamanbaeva, G., Mählmann, L., Brand, S., Beglinger, C., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01977-z · Cited by 280
“Two-thirds of depressed patients do not respond adequately to initial antidepressant medication [2] and up to 30% of treatment-resistant patients experience residual symptoms when receiving optimized treatments [3].”
Background
Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function
Cussotto, S., Strain, C. R., Fouhy, F., Strain, R. G., Peterson, V. L., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5006-5 · Cited by 266
The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study
Jaffe, D. H., Rive, B., & Denee, T. R. (2019) · BMC Psychiatry · doi:10.1186/s12888-019-2222-4 · Cited by 237
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Fu, D.-J., Ito, T., Kambarov, Y., Llorca, P.-M., Oliveira-Maia, A. J., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2304145 · Cited by 222
Socio-demographic and clinical predictors of non-response/non-remission in treatment resistant depressed patients: A systematic review
Carlo, V. D., Calati, R., & Serretti, A. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2016.04.034 · Cited by 219
Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier
Lee, D., & Minko, T. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13122049 · Cited by 227
Adult Neurogenesis and Psychiatric DisordersPreprint
Kang, E., Wen, Z., Song, H., Christian, K. M., & Ming, G. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019026 · Cited by 189
“Al-Harbi KS. 2012.”
Pharmacological interventions targeting anhedonia in patients with major depressive disorder: A systematic review
Cao, B., Zhu, J., Zuckerman, H., Rosenblat, J. D., Brietzke, E., Pan, Z., Subramanieapillai, M., Park, C., Lee, Y., & McIntyre, R. S. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.01.002 · Cited by 175
“Similar to SSRIs, agomelatine has been demonstrated to have beneficial effects on symptoms of depression.”
BackgroundInfluential
Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight
Singh, I., Morgan, C. J. A., Curran, V. H., Nutt, D., Schlag, A. K., & McShane, R. H. (2017) · The Lancet Psychiatry · doi:10.1016/s2215-0366(17)30102-5 · Cited by 162
“The literature on depression treatment suggests that 30% of patients are treatment-resistant [34].”
Background
Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway
Wang, J., Zhang, Y., Chen, Y., Wang, Y., Li, S., Wang, Y., ZHANG, Z.-X., Zhang, J., & Rong, P. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02341-6 · Cited by 164
Therapeutic Strategies for Treatment of Inflammation-related Depression
Adžić, M., Brkic, Z., Mitić, M., Francija, E., Jovicic, M. J., Radulović, J., & Marić, N. P. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170828163048 · Cited by 162
Machine learning in the prediction of depression treatment outcomes: a systematic review and meta-analysis
Sajjadian, M., Lam, R. W. M., Milev, R. V., Rotzinger, S., Frey, B. N., Soares, C. N., Parikh, S. V., Foster, J. A., Turecki, G., Müller, D. J., et al. (2021) · Psychological Medicine · doi:10.1017/s0033291721003871 · Cited by 168
“Each treatment trial takes between 6 and 12 weeks and the delays are associated with the risk of adverse outcomes, including loss of employment and suicide (Al-Harbi, 2012; Crown et al., 2002).”
Background
Mood disorders and complementary and alternative medicine: a literature review
Qureshi, N. A., & Al-Bedah (2013) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s43419 · Cited by 161
“12,13 Overall, 30%–40% of patients with major depression would benefit from CAM.”
Influential
Esketamine for treatment resistant depression
Swainson, J., Thomas, R. K., Archer, S., Chrenek, C., MacKay, M.-A., Baker, G., Dursun, S., Klassen, L. J., Chokka, P., & Demas, M. L. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1640604 · Cited by 151
The Role of Chemokines in the Pathophysiology of Major Depressive Disorder
Milenkovic, V. M., Stanton, E. H., Nothdurfter, C., Rupprecht, R., & Wetzel, C. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092283 · Cited by 149
“of patients diagnosed with MDD fail to respond to anti-depressant therapy, or show only a partial response [2,3].”
Background
Natural polyphenols in the management of major depression
Pathak, L., Agrawal, Y. K., & Dhir, A. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.794783 · Cited by 145
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 142
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
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
“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 135
“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
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
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 130
“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
Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review
Mura, G., Moro, M. F., Patten, S. B., & Carta, M. G. (2014) · CNS Spectrums · doi:10.1017/s1092852913000953 · Cited by 127
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 124
“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 116
“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
“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
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
Ketamine for depression
Jelen, L. A., & Stone, J. M. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2020.1854194 · Cited by 112
“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 108
“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 103
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
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
“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
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 99
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 94
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
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 87
“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 89
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
“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
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 87
“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 87
Understanding exosomes: Part 2—Emerging leaders in regenerative medicine
Miron, R. J., Estrin, N. E., Sculean, A., & Zhang, Y. (2024) · Periodontology 2000 · doi:10.1111/prd.12561 · Cited by 89
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
“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
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
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
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 81
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 83
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
“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
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
“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 80
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 84
“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 76
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
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 80
“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
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
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
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 71
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
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 72
“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. R. B., & Peixoto, C. A. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114153 · Cited by 73
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
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 68
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 67
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 67
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 65
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 64
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
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 60
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
“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
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 58
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 62
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 59
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 59
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 65
“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 59
“…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 62
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 61
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
“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
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 53
“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 58
“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 52
“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 51
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 54
Estimating Prevalence and Healthcare Utilization for Treatment-Resistant Depression in Japan: A Retrospective Claims Database Study
Mahlich, J., Tsukazawa, S., & Wiegand, F. (2017) · Drugs - Real World Outcomes · doi:10.1007/s40801-017-0126-5 · Cited by 51
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

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 (medical) › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks