Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review

Berger, William; Mendlowicz, Mauro V.; Marques-Portella, Carla; Kinrys, Gustavo; Fontenelle, Leonardo F.; Marmar, Charles R.; Figueira, Ivan

doi:10.1016/j.pnpbp.2008.12.004

Cited by 347Posttraumatic Stress Disorder ResearchSleep and related disordersMigration, Health and Trauma

Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review

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Berger, William, Mendlowicz, Mauro V., Marques-Portella, Carla, Kinrys, Gustavo, Fontenelle, Leonardo F., Marmar, Charles R., Figueira, Ivan·2009·Progress in Neuro-Psychopharmacology and Biological Psychiatry

DOI 10.1016/j.pnpbp.2008.12.004PMC PMC2720612

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Abstract

The selective serotonin reuptake inhibitors (SSRIs) are considered the first-line pharmacological treatment for PTSD. However, even when treated with this class of drugs, response rates rarely exceed 60% and less than 20-30% of the patients achieve full remission. The aim of this study was to address this limitation by systematically reviewing the options left for the treatment of PTSD when patients do not respond satisfactorily to or tolerate SSRIs. A systematic review covering all original articles, letters and brief reports published in any language until October 2008 was conducted through searches in the ISI/Web of Science, PubMed and PILOTS databases. The search terms included the pharmacological class of each agent or its generic name plus "PTSD" or "stress disorder" in the title, in the abstract or as a keyword. Sixty-three articles were selected, covering the following categories: antipsychotics, anticonvulsants, adrenergic-inhibiting agents, opioid antagonists, benzodiazepines and other agents. None of the identified agents reached the level A of scientific evidence, 5 reached level B, 7 level C and 13 level D. The non-antidepressant agent with the strongest scientific evidence supporting its use in PTSD is risperidone, which can be envisaged as an effective add-on therapy when patients did not fully benefit from previous treatment with SSRIs. Prazosin, an adrenergic-inhibiting agent, is a promising alternative for cases of PTSD where nightmares and insomnia are prominent symptoms. So far, there is no consistent empirical support for using benzodiazepines in the prevention or in the treatment of PTSD, although these drugs could alleviate some associated non-specific symptoms, such as insomnia or anxiety. Further controlled clinical trials and meta-analysis are needed to guide clinicians in their search of effective pharmacological alternatives to antidepressants in PTSD.

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20-30% of PTSD patients do not respond at all to treatment with the current gold standard of PTSD drug therapy, the serotonin re-uptake inhibitors.
“because 20–30% of PTSD patients do not respond at all to treatment with the current gold standard of PTSD drug therapy, the serotonin re-uptake inhibitors [7].”
From Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial (2017) · cites this paper as [7]

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Benzodiazepines for PTSD: A Systematic Review and Meta-Analysis
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Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values
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Treatment of Nightmares With Prazosin: A Systematic Review
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A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder
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Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service–Related PTSD
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Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex
Shansky, R. M., & Lipps, J. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00123 · Cited by 205 · see citing works
“From a translational standpoint, this is problematic; stressrelated mental illnesses like post-traumatic stress disorder (PTSD) and major depressive disorder are twice as prevalent in women (Becker et al., 2007), suggesting a distinct neurobiology may underlie the stress response in female brains.”
Background
Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies
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Pharmacological treatment of PTSD – Established and new approaches
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Dysregulation of Inflammation, Neurobiology, and Cognitive Function in PTSD: An Integrative Review
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Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder
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Posttraumatic Stress Disorder and Stress-Related Disorders
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Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence
Petrakis, I. L., Ralevski, E., Desai, N., Trevisan, L. A., Gueorguieva, R. V., Rounsaville, B. J., & Krystal, J. H. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.283 · Cited by 122 · see citing works
The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding
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Evidence‐based treatments for PTSD, new directions, and special challenges
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Biomarkers in Posttraumatic Stress Disorder: Overview and Implications for Future Research
Schmidt, U., Kaltwasser, S. F., & Wotjak, C. T. (2013) · Disease Markers · doi:10.1155/2013/835876 · Cited by 100 · see citing works
Is there tonic immobility in humans? Biological evidence from victims of traumatic stress
Volchan, E., Souza, G. G., Franklin, C. M., Norte, C. E., Rocha-Rego, V., Oliveira, J. M., David, I. A., Mendlowicz, M. V., Coutinho, E. S. F., Fiszman, A., et al. (2011) · Biological Psychology · doi:10.1016/j.biopsycho.2011.06.002 · Cited by 101 · see citing works
Self-citation
Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients
Zaba, M., Kirmeier, T., Ionescu, I. A., Wollweber, B., Buell, D. R., Gall-Kleebach, D. J., Schubert, C. F., Novak, B., Huber, C., Köhler, K., et al. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.02.005 · Cited by 101 · see citing works
Randomized controlled trials of psychological and pharmacological treatments for nightmares: A meta-analysis
Augedal, A. W., Hansen, K. S., Kronhaug, C. R., Harvey, A. G., & Pallesen, S. (2013) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2012.06.001 · Cited by 98 · see citing works
Methylation of FKBP5 and SLC6A4 in relation to treatment response to mindfulness based stress reduction for posttraumatic stress disorder
Bishop, J. R., Lee, A. M., Mills, L. J., Thuras, P. D., Eum, S., Clancy, D., Erbes, C. R., Polusny, M. A., Lamberty, G. J., & Lim, K. O. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00418 · Cited by 98 · see citing works
PTSD Treatment for Veterans: What's Working, What's New, and What's Next.
Reisman, M. (2016) · PubMed Central · Cited by 97 · see citing works
Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials
de Bitencourt, R. M., & Takahashi, R. N. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00502 · Cited by 98 · see citing works
Emotion Regulatory Brain Function and SSRI Treatment in PTSD: Neural Correlates and Predictors of Change
MacNamara, A., Rabinak, C. A., Kennedy, A. E., Fitzgerald, D. A., Liberzon, I., Stein, M. B., & Phan, K. L. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.190 · Cited by 90 · see citing works
Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis – related proteins in a rat model of post-traumatic stress disorder
Shafia, S., Vafaei, A. A., Samaei, S. A., Bandegi, A. R., Rafiei, A., Valadan, R., Hosseini-Khah, Z., Mohammadkhani, R., & Rashidy-Pour, A. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.01.009 · Cited by 89 · see citing works
Recent Progress in Understanding the Pathophysiology of Post-Traumatic Stress Disorder: Implications for Targeted Pharmacological Treatment
Bailey, C. R., Cordell, E., Sobin, S. M., & Neumeister, A. (2013) · CNS Drugs · doi:10.1007/s40263-013-0051-4 · Cited by 89 · see citing works
Immobility reactions under threat: A contribution to human defensive cascade and PTSD
Volchan, E., Rocha-Rego, V., Bastos, A. F., Oliveira, J. M., Franklin, C., Gleiser, S., Berger, W., Souza, G. G. L., Oliveira, L., David, I. A., et al. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.025 · Cited by 87 · see citing works
Self-citation
Effects of Pharmacotherapy on Combat-Related PTSD, Anxiety, and Depression: A Systematic Review and Meta-Regression Analysis
Puetz, T. W., Youngstedt, S. D., & Herring, M. P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126529 · Cited by 86 · see citing works
Real-time fMRI neurofeedback with War Veterans with chronic PTSD: a feasibility study
Gerin, M. I., Fichtenholtz, H., Roy, A., Walsh, C. J., Krystal, J. H., Southwick, S., & Hampson, M. (2016) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2016.00111 · Cited by 84 · see citing works
The impact of tonic immobility reaction on the prognosis of posttraumatic stress disorder
Lima, A. A., Fiszman, A., Marques-Portella, C., Mendlowicz, M. V., Coutinho, E. S. F., Maia, D. C. B., Berger, W., Rocha-Rego, V., Volchan, E., Mari, J. J., et al. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2009.08.005 · Cited by 82 · see citing works
Self-citation
Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder
Solanki, N., Alkadhi, I., Atrooz, F., Patki, G., & Salim, S. (2014) · Nutrition Research · doi:10.1016/j.nutres.2014.11.008 · Cited by 81 · see citing works
The Psychedelic Future of Post-Traumatic Stress Disorder Treatment
Zaretsky, T. G., Jagodnik, K. M., Barsic, R., Antonio, J. H., Bonanno, P. A., MacLeod, C., Pierce, C., Carney, H., Morrison, M. T., Saylor, C. F., et al. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666231027111147 · Cited by 85 · see citing works
Comparing the Effect of Prazosin and Hydroxyzine on Sleep Quality in Patients Suffering from Posttraumatic Stress Disorder
Ahmadpanah, M., Sabzeiee, P., Hosseini, S. M., Torabian, S., Haghighi, M., Jahangard, L., Bajoghli, H., Holsboer‐Trachsler, E., & Brand, S. (2014) · Neuropsychobiology · doi:10.1159/000362243 · Cited by 80 · see citing works
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Authors: Berger, W., Mendlowicz, M. V., Marques-Portella, C., Kinrys, G., Fontenelle, L. F., Marmar, C. R., & Figueira, I.
Affiliations: Universidade Federal do Rio de Janeiro (BR)
Cambridge Health Alliance (US)
San Francisco VA Medical Center (US)
Corresponding author: Berger, William
ORCID: Berger, William
Mendlowicz, Mauro V.
Kinrys, Gustavo
Fontenelle, Leonardo F.
Marmar, Charles R.
Figueira, Ivan
Venue: Progress in Neuro-Psychopharmacology and Biological Psychiatry
Publisher: Elsevier BV
Published: 2009-03
Volume: 33
Issue: 2
Pages: 169-180
ISSN: 0278-5846 (ISSN-L)
DOI: 10.1016/j.pnpbp.2008.12.004
PMC: PMC2720612
OpenAlex: W1977428298
Cited by: 347
References: 137
Citations by year: 2026: 14 · 2025: 12 · 2024: 29 · 2023: 26 · 2022: 28 · 2021: 41 · 2020: 27 · 2019: 15 · 2018: 24 · 2017: 12 · 2016: 17 · 2015: 16 · 2014: 16 · 2013: 17 · 2012: 18
FWCI: 2.01
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Australian Government
Governo Brasil
National Institute of Mental Health (MH056350-06, R01MH056350)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Social Sciences › Psychology › Clinical Psychology › Migration, Health and Trauma
Keywords: post-traumatic stress disorder, pharmacotherapy, antidepressants, selective serotonin reuptake inhibitors, risperidone, prazosin, benzodiazepines, antipsychotic drugs, antiepileptic drugs, opioid antagonists, treatment-resistant PTSD, nightmares, insomnia, adjunctive therapy
MeSH terms: Animals, Anticonvulsants, Antidepressive Agents, Benzodiazepines, Humans, Narcotic Antagonists, Stress Disorders, Post-Traumatic, Antipsychotic Agents, Adrenergic Antagonists

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Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: A systematic review

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