ArticleLiterature Review

Psychopharmacological Strategies in the Management of Posttraumatic Stress Disorder (PTSD): What Have We Learned?

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Abstract

There have been significant advancements in the pharmacologic management of posttraumatic stress disorder (PTSD) in the past two decades. Multisite randomized clinical trials (RCTs) have noted the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNR Is) for PTSD treatment. Unfortunately, there have been no new medications approved to treat PTSD in the past 10 years. Although there have been exciting new findings in our knowledge of the neurobiology of PTSD, clinical trials testing new medications have lagged. This review summarizes recent research that builds on the unique pathophysiology of PTSD and suggests ways to move the field forward.

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... This suggests that psychobiological processing of TE may be more decisive for the subsequent PTSD development than TE itself (Bandelow et al., 2017;Walker, Pfingst, Carnevali, Sgoifo, & Nalivaiko, 2017). However, PTSD prevalence of nearly 100% was found in severe traumatized populations, meaning that indeed any individual may develop PTSD once TE is extremely high (Conrad et al., 2017;Kolassa, Kolassa, Ertl, Papassotiropoulos, & De Quervain, 2010;Neuner et al., 2004 Richardson et al., 2017;Spinhoven, Penninx, van Hemert, de Rooij, & Elzinga, 2014), long symptom persistence (Kessler et al., 2017;Morina, Wicherts, Lobbrecht, & Priebe, 2014), and still insufficient treatment methods (e.g., Bernardy & Friedman, 2015;Carpenter et al., 2018;Visser, Gosens, Den Oudsten, & De Vries, 2017). These show the importance of further elucidating psychobiological mechanisms underlying the development and maintenance of PTSD. ...
... An exposure to extreme, traumatic stress has been found to be strongly associated with psychopathology (e.g., Sayed, Iacoviello, & Charney, 2015;Walker et al., 2017), especially with a subsequent development of posttraumatic stress disorder (PTSD) in a proportion of exposed individuals (Breslau, 2009;Kessler et al., 2017). Identifying pre-, peri-, and post-trauma indicators associated with disease intensity may help to understand its psychobiological mechanisms (Bandelow et al., 2017;Schmidt et al., 2015) as well as to optimize still insufficient diagnosis and treatment strategies (Bernardy & Friedman, 2015;Jonas et al., 2013;Visser et al., 2017). ...
... mind may help to improve clinical outcomes of the sufferers and to reduce the large individual and societal burden of PTSD (e.g.,Bernardy & Friedman, 2015;Jonas et al., 2013;Visser, Gosens, Den Oudsten, & De Vries, 2017).Manifestation of PTSD can be seen as a pathological response to extreme stress being outside the range of usual human experience. For this reason, there is a long tradition of studying the hypothalamus-pituitary-adrenal (HPA)-axis, the body's major neuroendocrine stress response system, dysregulations in the context of TE and PTSD research. ...
... Indeed, only about half of patients respond to SSRIs and more than a third of SSRI-treated patients fail to respond, do not reach full remission, or even develop SSRI resistance (Bernardy and Friedman, 2015;Golden et al., 2002;Kemp et al., 2008;Rush et al., 2006). Furthermore, most patients who initially respond to SSRI treatment fail to maintain therapeutic gains over time. ...
... Collectively, current pharmacotherapy for PTSD relies mostly on fluoxetine, paroxetine, sertraline and venlafaxine alone or in combination with PE. The beneficial therapeutic gains are modest with all of these, (Bernardy and Friedman, 2015;Locci and Pinna, 2017a), hence, the development of new agents that act through different mechanisms (rather than inhibition of serotonin reuptake) or new therapeutic strategies that can help treatment-resistant patients, is needed. This also suggests the need to develop biomarker-based therapy designed for specific trauma-exposed individuals who develop PTSD and fail to respond to traditional treatments (Pinna and Izumi, 2018). ...
... The therapeutic relevance of cannabinoids for PTSD has been the focus of several debates. Cannabis is often used as a self-medication by patients (Bernardy and Friedman, 2015;Bonn-Miller et al., 2014;Cougle et al., 2011;Earleywine and Bolles, 2014), which is primarily composed of THC and cannabidiol (CBD) (Bergamaschi et al., 2011;Budney et al., 2004). This is likely facilitated by a greater cannabinoid receptor density in patients with PTSD (Neumeister et al., 2013). ...
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Fear is an emotion that serves as a driving factor in how organisms move through the world. In this review, we discuss the current understandings of the subjective experience of fear and the related biological processes involved in fear learning and memory. We first provide an overview of fear learning and memory in humans and animal models, encompassing the neurocircuitry and molecular mechanisms, the influence of genetic and environmental factors, and how fear learning paradigms have contributed to treatments for fear-related disorders, such as posttraumatic stress disorder. Current treatments as well as novel strategies, such as targeting the perisynaptic environment and use of virtual reality, are addressed. We review research on the subjective experience of fear and the role of autobiographical memory in fear-related disorders. We also discuss the gaps in our understanding of fear learning and memory, and the degree of consensus in the field. Lastly, the development of linguistic tools for assessments and treatment of fear learning and memory disorders is discussed.
... Further, they are key synthons for the synthesis of various fused ring compounds [2,3]. As such, further development of BZDs has gained significant attention of organic and medicinal chemists in a quest to discover new and efficacious benzodiazepine based therapeutic agents [4]. ...
... Benzodiazepines have been the subject of previous reviews. Recently, Varvounis et al., published a review describing the synthesis of pyrrolo [2,1-c] [1,4]benzodiazepines, whereas Sathish et al. reviewed the synthesis and biological activities of benzodiazepam derivatives [52,53]. Mantaj et al. published a review describing the developments from anthramycin to pyrrolobenzodiazepine (PBD)-containing antibody-drug conjugates as anticancer agents [54]. ...
... Synthetic applications of metal-organic frameworks (MOFs) possessing Lewis acid sites (LAS) as metallic centers in their structures for the cyclocondensation of acetone with different 1,2-diamines have been explored as valuable heterogeneous catalysts to achieve the synthesis of biologically active 1,5-benzodiazepines. Further, calix [4]arenes with acidic groups were successfully employed as acid catalysts for the synthesis of heterocycles. Isaeva et al., in this study explored the catalytic properties of novel nanoporous materials (MIL/K-SO 3 H and MIL/ Ks-CN) by developing highly efficient microwave-assisted one-pot synthesis of 1,5-benzodiazepines via encapsulation of para-sulfonatocalixarene (K-SO 3 H) and para-tert-butylthiacalix- [4]-arene (Ks-CN) with strong (-SO 3 H) and weak (-CN) acidic functionalities, respectively, in the metal-organic framework (NH 2 -MIL-101(Al)) cavities (Scheme 2 & Fig. 4). ...
Article
Benzodiazepines (BZDs) represent a diverse class of bicyclic heterocyclic molecules. In the last few years, benzodiazepines have emerged as potential therapeutic agents. As a result, several mild, efficient and high yielding protocols have been developed that offer access to various functionalized benzodiazepines (BZDs). They are known to possess a wide array of biological activities such as anxiolytic, anticancer, anticonvulsant, antipsychotics, muscle relaxant, anti-tuberculosis, and antimicrobial activities. The fascinating spectrum of biological activities exhibited by BZDs in various fields has prompted the medicinal chemist to design and discover novel benzodiazepine-based analogs as potential therapeutic candidates with the desired biological profile. In this review, an attempt has been made by to summarize (1) Recent advances in the synthetic chemistry of benzodiazepines which enable their synthesis with desired substitution pattern; (2) Medicinal chemistry of BZDs as therapeutic candidates with promising biological profile including insight of mechanistic studies; (3) The correlation of biological data with the structure i.e. structure-activity relationship studies were also included to provide an insight into the rational design of more active agents.
... The British Association for Psychopharmacology Guidelines (Baldwin et al., 2014) recommended RIS or OLZP after antidepressant optimization, switching antidepressants and combination of antidepressants with trauma focused psychotherapy prove ineffective; and the latest edition of the Canadian Psychiatric Association Treatment Guidelines for PTSD (Katzman et al., 2014) also recommends RIS and OLZP as second line adjunctive therapy, ARIP as third adjunctive therapy, and state that OLZP cannot be recommended as monotherapy. Hoskins et al. (2015), in the very recently completed meta-analysis of all RCTs in PTSD commissioned by the WHO, found only the negative Krystal et al. (2011) trial met their inclusion criteria for RCTs, thus finding no evidence for SGA AUG of AD; and Bernardy and Friedman (2015) found the evidence for SGA AUG of AD mixed. In summary, while the majority of reviewers recommend SGA augmentation of antidepressants in PTSD patients who fail one or more adequate trials (and have either failed, cannot, or will not engage in trauma focused psychotherapy), there are many heterogenous findings in these reviews relevant to understanding their role in TRPTSD: 1) Several reviewers specifically recommend an SGA augmentation trial in patients with PTSD + PF who fail antidepressants, while recommendations for SGA augmentation in non-psychotic patients are mixed. ...
... Before the SGA era, these agents were widely used for patients with perceptual disturbances comprising severe re-experiencing symptoms, with limited benefit. The VA/DoD, ISTSS and Harvard South reviews of psychopharmacology in PTSD did not find these agents worth recommending for any reason, and Bernardy and Friedman (2015) did not recommend them as monotherapy. Of note, however, Pivac and Kozarić-Kovacić (2006) described three 6 week OLIs of inpatients with PTSD + PF who had not benefitted from other treatments including 2 sequential 8 week trials of different antidepressants, as well as "sedative-hypnotics" and anticonvulsants, and compared outcomes with fluphenazine (FPH; N = 27), olanzapine (OLZP; N = 28), risperidone (RIS; N = 26), or quetiapine (QUET; N = 53). ...
... Bajor et al. (2011), in some contrast to other guidelines, recommend PRAZ as the first line pharmacotherapy in PTSD, before SSRIs, if sleep disturbances are significant enough to require treatment before/while patients undergo trauma focused psychotherapy. The findings of Bernardy and Friedman (2015) were in accord with Bajor et al. (2011). Jeffreys et al. (2012) and Kerbage and Richa (2015) both found evidence to support the efficacy of prazosin for sleep/nightmares, while Ipser and Stein (2012) recommended PRAZ for sleep and nightmares unresponsive to SSRIs. ...
... For example, a case report of TRPTSD noted that switching to venlafaxine resulted in improvement even after several SSRIs failed [38]. More robust confirmation of this encouraging finding is needed, but as this strategy carries little additional risk, and SSRIs and venlafaxine remain the most evidence-based pharmacological treatment options for PTSD [8••, 9, 28•], empirical trials seem acceptable pending further investigation as to the most effective sequence of antidepressants [12,26]. ...
... The combination of a first-line antidepressant, such as an SSRI, with a firstline psychotherapy, such as PE, after a poor response to either alone, is a third approach with empirical support. Even when not able to produce remission, antidepressants can reduce the intensity of symptoms [12], particularly anxiety, which may allow patients to successfully complete exposure therapy if it has previously been intolerable. It is attractive to imagine that combining two efficacious treatments results in an even more effective overall treatment, but the evidence for this approach is mixed. ...
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Opinion statement Purpose of review The management of treatment-resistant posttraumatic stress disorder (TRPTSD) is a complex clinical challenge, and many patients may continue to endure a heavy symptom burden, even despite the best available treatments. We review the recent literature to provide an update on the evidence base and offer guidance to clinicians on available approaches, including a number of novel and emerging options. Recent findings If adequate trials of treatment with first-line antidepressants (SSRIs or venlafaxine) or trauma-focused psychotherapy have failed, dosage increase, switching to an alternative first-line option, or combining medication and psychotherapy are reasonable initial approaches. If these remain insufficient, augmentation strategies should be offered, including addition of second-generation antipsychotics (such as risperidone) or the adrenergic antagonist prazosin (especially if sleep disturbance or nightmares are problematic). Further options include the use of other antidepressants (most notably mirtazapine, duloxetine, and trazodone), and the anticonvulsants topiramate or lamotrigine, though the evidence for these is relatively weak. Having tried all these possibilities, the clinician may wish to suggest complementary approaches such as yoga, mindfulness meditation, or acupuncture for symptom reduction and overall well-being. Emerging alternatives, if available, could also be considered, such as augmentation of exposure therapy with d-cycloserine or MDMA, or the use of device-based brain stimulation (such as transcranial magnetic stimulation), though the evidence for these is still preliminary. Summary Comprehensive assessment of TRPTSD, including a thorough evaluation of associated comorbidity, should inform individualized care, incorporating a process of shared decision-making. Despite the complex clinical challenge of TRPTSD, clinicians should remain hopeful however, that translational neuroscience and clinical trials of emerging approaches will allow progressively better treatment alternatives to be established.
... 56 Venlafaxine, which inhibits the reuptake of serotonin at lower doses, as well as norepinephrine at higher doses, also is a first-line pharmacological approach for treating PTSD, although venlafaxine has not been FDA-approved for this indication. [57][58][59] It is important, however, to consider that meta-analysis demonstrates only small to medium effect sizes for the difference in performance between SSRIs or SNRIs and placebo. 60 Thus, it may be difficult to discern whether symptom improvement in an individual patient is attributable to active drug, placebo effect, or other factors related to engagement in PTSD treatment. ...
... The substantial rate of resistance to the potential therapeutic effect of SSRIs initially appeared to be related to male sex or veteran status; more recent overviews of SSRI treatment studies in PTSD suggest that resistance may be related to age, illness chronicity, 59 or possibly to ethnicity. Both SSRIs and venlafaxine are generally safe, although each may be associated with particular side effects. ...
Article
The events leading to traumatic brain injury (TBI) are often psychologically traumatic (e.g., motor vehicle accidents) or occur within a broader context of psychological trauma, such as military combat or recurrent interpersonal violence. In such cases, posttraumatic stress disorder (PTSD) may develop and serve to complicate TBI recovery. Likewise, brain trauma may impede emotional resolution following psychological trauma exposure. This article addresses comorbid PTSD and TBI, including the epidemiology of PTSD following TBI; the clinical presentation of the comorbidity; potential mechanisms that complicate recovery from psychological trauma and TBI when they co-occur; and considerations for the clinical management of PTSD in the context of TBI, including implications for both psychosocial and psychopharmacological PTSD treatments. Although the authors address the full spectrum of TBI severity, because PTSD more commonly co-occurs with mild TBI, compared with moderate and severe TBI, the authors focus in particular on mild TBI.
... Current pharmaco-treatment for PTSD relies in the administration of the selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and sertraline, the only FDA-approved drugs for PTSD (Friedman and Bernardy, 2017). These drugs are associated with poor response rate in a consistent number of treatment-seeking patients, with active military members and veterans who are relatively non-responsive to SSRIs (Bernardy and Friedman, 2015;Starke and Stein, 2017). Developing suitable animal models for PTSD and discovering reliable biomarkers that allow a more accurate diagnosis, based on objective measures, may improve quality of healthcare. ...
... The finding that the traditional gold-standard treatment option for PTSD, the selective serotonin reuptake inhibitors (SSRIs), is efficient in about half of the treated patients (reviewed in Golden et al., 2002;Rush et al., 2006;Kemp et al., 2008;Bernardy and Friedman, 2015), suggests that mood disorders emerge from complex neurobiological backgrounds and only one molecular deficit may not reflect a valid biomarker for the disorder under examination. Likewise, only one treatment cannot be the answer to improve symptoms in all patients, following the one-fit-all treatment expectation (Brewin, 2001;Aspesi and Pinna, 2018). ...
Article
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Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%-13% of the general population and 20%-30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABA A receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABA A receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.
... This impact is aggravated by the scarcity of psychological and, above all, pharmacological approaches to PTSD treatment (Hidalgo and Davidson, 2000;Yule, 2001;Jurkus et al., 2016). At present, approved treatments for PTSD involve anxiolytics and antidepressants, which are inefficient and have considerable side effects (Berger et al., 2009;Shin et al., 2014;Bernardy and Friedman, 2015). ...
... That the available drugs (such as antidepressants and anxiolytics) do not specifically target the memory process may be one of the reasons that pharmacological treatment of PTSD is so difficult (Singewald et al., 2015). Currently approved treatments for PTSD include SSRIs and serotonin/noradrenaline reuptake inhibitors, both with low efficacy (Bernardy and Friedman, 2015). The response rate for SSRIs rarely exceeds 60%, of which less than 30% represents complete remission (Berger et al., 2009). ...
Article
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Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects. Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD. Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system. These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well. Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD. The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.
... Paroxetine and sertraline are currently the only Food and Drug Administration-approved drugs to treat PTSD symptoms (Friedman and Bernardy, 2017). Recent studies reveal a considerable variability in their efficacy, often with the resistant individuals, such as veterans (Bernardy and Friedman, 2015;Starke and Stein, 2017), who need augmentation or various combination of treatments (Stein et al., 2009). As the response rate to SSRIs rarely exceeds 40-60%, research on discovering new treatments has become a priority. ...
... Thus, traumas in specific and susceptible periods of the PTSD patient's life can predict if they will respond successfully to treatment with SSRIs. Furthermore, veterans who suffer from PTSD are particularly resistant to SSRI treatment (Bernardy and Friedman, 2015). ...
Article
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Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.
... CBT is a time-limited therapy that involves setting specific treatment goals and working towards the remediation of problematic symptoms. CBT treatments have been specifically designed for PTSD symptoms, and have demonstrated particularly strong empirical support and, subsequently, have been designated as evidence-based interventions for PTSD (Bernardy and Friedman 2015). These treatments include, but are not limited to, exposure therapy (Foa and Rothbaum 1998), cognitive processing therapy (Resick et al. 2010) and Imagery Rehearsal Therapy (Moore and Krakow 2010). ...
... In addition to CBT treatments, research in pharmacotherapy for PTSD has indicated that antidepressant and anxiolytic medications have been effective, specifically the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs; Bernardy and Friedman 2015). The efficacy of SSRIs and other antidepressant medications is due primarily to the overlap of PTSD symptoms with those of depression and many anxiety disorders, and it has been suggested that SSRI or SNRI treatments are especially effective for PTSD symptoms such as irritability, anger, anxiety and depression (Shiromani et al. 2012). ...
Article
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The aim of this study was to estimate the prevalence and probabilities of comorbidities between self-reported PTSD and smoking, alcohol binge drinking and substance use disorders (SUDs) from a national Canadian sample. Data were taken from the Statistics Canada Public Use Microdata File of the 2012 Canadian Community Health Survey–Mental Health (n = 17,311). The prevalence of (a) smoking, (b) alcohol binge drinking and (c) SUDs was estimated among those with a PTSD diagnosis versus those without a PTSD diagnosis. After controlling for potential socioeconomic and mental health covariates, self-reported PTSD acted as a significant predictor for membership in the heaviest smoking, alcohol, and substance use categories. Individuals self-reporting a diagnosis of PTSD have a significantly higher likelihood of engaging in smoking and alcohol binge drinking, and are more likely to meet criteria for SUDs than individuals not reporting a PTSD diagnosis.
... Over 50% of patients with posttraumatic stress disorder (PTSD) also suffer from the major depressive disorder (MDD; Flory & Yehuda, 2015;Rytwinski, Scur, Feeny, & Youngstrom, 2013). Unfortunately, first-line treatments are less effective in these patients (Bernardy & Friedman, 2015;Chase et al., 2017;Nixon & Nearmy, 2011). Given that long-term prognoses are generally poorer for patients with comorbid presentations (Flory & Yehuda, 2015), the generation and optimization of new treatment alternatives is a high research priority. ...
Article
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Background: Recent evidence suggests that therapeutic repetitive transcranial magnetic stimulation (TMS) is an effective treatment for pharmacoresistant posttraumatic stress disorder (PTSD) and comorbid major depressive disorder (MDD). We recently demonstrated that response to 5 Hz TMS administered to the dorsolateral prefrontal cortex was predicted by functional connectivity of the medial prefrontal (MPFC) and subgenual anterior cingulate cortex (sgACC). This functionally-defined circuit is a novel target for treatment optimization research, however, our limited knowledge of the structural pathways that underlie this functional predisposition is a barrier to target engagement research. Methods: To investigate underlying structural elements of our previous functional connectivity findings, we submitted pre-TMS diffusion-weighted imaging data from 20 patients with PTSD and MDD to anatomically constrained tract-based probabilistic tractography (FreeSurfer's TRActs Constrained by UnderLying Anatomy). Averaged pathway fractional anisotropy (FA) was extracted from four frontal white matter tracts: the forceps minor, cingulum, anterior thalamic radiations (ATRs), and uncinate fasciculi. Tract FA statistics were treated as explanatory variables in backward regressions testing the relationship between tract integrity and functional connectivity coefficients from MPFC and sgACC predictors of symptom improvement after TMS. Results: FA in the ATRs was consistently associated with symptom improvement in PTSD and MDD (Bonferroni-corrected p < .05). Conclusion: We found that structural characteristics of the ATR account for significant variance in individual-level functional predictors of post-TMS improvement. TMS optimization studies should target this circuit either in stand-alone or successive TMS stimulation protocols.
... Approximately one-half of patients with PTSD are diagnosed of MDD [32,33], and these patients were reported to demonstrate a poorer response to antidepressant treatment [34,35] and a more chronic course of functional impairment [36] than are those with PTSD or MDD alone. Previous studies have provided some evidence supporting the therapeutic effect of rTMS on PTSD [37]. ...
Article
Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) are evidenced-based treatments for patients with major depressive disorder (MDD) who fail to respond to standard first-line therapies. However, although various TMS protocols have been proven to be clinically effective, the response rate varies across clinical applications due to the heterogeneity of real-world psychiatric comorbidities, such as generalized anxiety disorder, posttraumatic stress disorder, panic disorder, or substance use disorder, which are often observed in patients with MDD. Therefore, individualized treatment approaches are important to increase treatment response by assigning a given patient to the most optimal TMS treatment protocol based on his or her individual profile. This literature review summarizes different rTMS or TBS protocols that have been applied in researches investigating MDD patients with certain psychiatric comorbidities and discusses biomarkers that may be used to predict rTMS treatment response. Furthermore, we highlight the need for the validation of neuroimaging and electrophysiological biomarkers associated with rTMS treatment responses. Finally, we discuss on which directions future efforts should focus for developing the personalization of the treatment of depression with rTMS or iTBS.
... According to the DSM-5, PTSD is relocated from the anxiety disorders category to a new diagnostic category named "Trauma and Stressor-related Disorders". The necessary conditions in order to develop PTSD are: direct or indirect exposure to a strong trauma, frequent involuntary and intrusive memories of the experienced trauma, persistent avoidance and denial of everything related to the trauma, general negative emotional state with constant feelings of fear, horror, anger, guilt or shame towards the world, irritable behavior, hypervigilance, exaggerated startle response, concentration problems, sleep difficulties [70]. Unfortunately there are no effective pharmacological or psychological treatments for PTSD [71]. ...
Article
The pharmacological research on the Cannabis sativa-derived compounds has never terminated. Among the phytocannabinoids without psychotropic effects, the prevalent one in Cannabis is cannabidiol (CBD). Although CBD was initially considered a type 2 cannabinoid receptor (CB2R) antagonist, it did not show a good cannabinoidergic activity. Furthermore, heterogeneous results were obtained in experimental animal models of anxiety disorders, psychotic stages and neurodegenerative diseases. Recently, CBD has been authorized by the FDA to treat some rare forms of epilepsy and many trials have begun for the treatment of autism spectrum disorders. This review aims to clarify the pharmacological activity of CBD and its multiple therapeutic applications. Furthermore, critical and conflicting results of the research on CBD are discussed with a focus on promising future prospects.
... Medication is provided to patients for symptomatic treatment, antidepressants are often the first line. These include medication classes such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and atypical antidepressants [18]. These medications are not only important for PTSD but also the associated conditions of depression and quality of life disability [19]. ...
... In den letzten Jahren wurde unterschiedlichen Theorien folgend eine Vielzahl von Substanzen auf ihre potentielle Wirksamkeit untersucht (67,68 (75). Aktuell befinden sich deshalb weitere Studien zu spezifischen psychopharmakologischen Strategien in Arbeit, die die individuelle Pathophysiologie und den richtigen Zeitpunkt eines eventuellen Medikationseinsatzes berücksichtigen (76). ...
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Die zentralen Bausteine der Diagnostik einer Posttraumatischen Belastungsstörung (PTBS) sind die Erfassung der traumatischen Ereignisse sowie die assoziierten Folgen auf symptomatischer und funktionaler Ebene. Für die Diagnosestellung nach der International Statistical Classification of Diseases and Related Health Problems (ICD-10) [16] sind die dort definierten Kriterien und für die funktionale Gesundheit das Klassifikationssystem der Internationalen Klassifikation der Funktionsfähigkeit, Behinderung und Gesundheit (ICF) relevant [17]. Dabei sollte die spezifische Diagnosestellung der PTBS in eine Gesamtdiagnostik eingebettet sein, welche die Aus- und Nachwirkungen auf die aktuelle Lebenssituation, komorbide Symptome sowie Chronifizierungsfolgen erfasst, aber auch salutogenetische Faktoren und den prätraumatischen Status erfragt. Über die Diagnose hinaus sollten sowohl die resultierenden Beeinträchtigungen der Aktivität und Teilhabe als auch die allgemeinen (Familien-, Wohn- und Arbeitssituation, regionale medizinische/psychotherapeutische Versorgung, gesundheitlicher Status) und spezifischen Kontextfaktoren erhoben werden. Hierzu gehören z. B. Täterkontakte, dependente Gewaltbeziehungen sowie z. B. der Rechts- und Aufenthaltsstatus bei Flüchtlingen [18]. Als Prozedere bei der Diagnostik wird häufig die folgende Sequenz eingehalten: Erhebung der Traumavorgeschichte sowie der Spontansymptomatik in der Anamnese, Durchführung eines Fragebogentests als Screening der Symptomintensität sowie bei entsprechender Indikation die Durchführung eines diagnostischen Interviews [2]. Ergänzend sollte potenziell bestehende Komorbidität explizit berücksichtigt und erfasst werden. Bei der Traumaanamnese (Erhebung früherer traumatischer Erfahrungen und Indextrauma) ist es in der Regel initial nicht notwendig bzw. indiziert Details der traumatischen Erfahrung zu explorieren, sondern ausreichend, eine kurze Beschreibung des Erlebten zu erheben. Ein Beharren auf detaillierten Beschreibungen während der ersten Interaktionsphase kann sich potenziell negativ auf die Therapie- und Beziehungsgestaltung auswirken [3].
... As mentioned above, the mainstay of current PTSD treatment includes psychological therapy, CBT, and eye movement desensitization and reprocessing as well as use of antidepressant medications. However, only 20-30% of PTSD patients achieve complete remission, while the remaining 70-80% continues to be refractory to these treatment modalities [65]. Current investigations into novel therapies for treatment-refractory PTSD focus on modulation of the neuroanatomical, pathophysiological and molecular substrates of PTSD. ...
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Posttraumatic Stress Disorder (PTSD) is a devastating condition that can develop after blast Traumatic Brain Injury (TBI). Ongoing work has been performed to understand how PTSD develops after injury. In this review, we highlight how PTSD affects individuals, discuss what is known about the physiologic changes to the hypothalamic pituitary axis and neurotransmitter pathways, and present an overview of genetic components that may predispose individuals to developing PTSD. We then provide an overview of current treatment strategies to treat PTSD in veterans and present new strategies that may be useful going forward. The need for further clinical and pre-clinical studies is imperative to improve diagnosis, treatment, and management for patients that develop PTSD following blast TBI.
... The serotonin selective reuptake inhibitors (SSRIs) sertraline and paroxetine, the only two FDA-approved medications for the treatment of PTSD, showed only moderate effect sizes in FDA registration trials (Brady et al. 2000;Davidson et al. 2001;Marshall et al. 2001;Tucker et al. 2001). Combat veterans, in particular, appeared to be resistant to SSRIs (e.g., Friedman et al. 2007), although variability in outcomes across veteran studies now suggests that ethnicity, age, or other subpopulation differences may play a role (Bernardy and Friedman 2015). The growing evidence for biological heterogeneity underlying the PTSD phenotype has therefore provoked a call for medications that address individually variable PTSD-specific pathophysiological processes (Rasmusson and Abdallah 2015;Friedman and Bernardy 2016). ...
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Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.
... Thus, treatments adapted to complement other interventions are advisable. For example, the following may help to reduce risk of SI: inclusion of psychoeducation related to sleep disturbances and PTSD, psychotherapy to target nightmares, such as nightmare rescripting or imagery rehearsal therapy [56,57], cognitive-behavioural therapy for insomnia [58], use of pharmacotherapy such as prazosin for trauma related nightmares [59][60][61] or risperidone [62], or low-dose sedating antidepressants or hypnotics [63][64][65]. These treatments may provide additional gains and increased quality of life among individuals struggling with sleep problems and mental disorders. ...
Article
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Background Past research on the association between insomnia and suicidal ideation (SI) has produced mixed findings. The current study explored the relationship between insomnia, SI, and past-year mental health status among a large Canadian Forces (CF) sample. Method Data was obtained from the 2013 Canadian Forces Mental Health Survey (CFMHS), and included a large representative sample of Canadian Regular Forces personnel (N = 6700). A series of univariate logistic regressions were conducted to test individual associations between past-year mental health status, insomnia, and potential confounds and SI. Mental health status included three groups: 0, 1, or two or more probable diagnoses of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD) and alcohol abuse/dependence. Stepwise multivariate logistic regression was used to assess the relationship between insomnia and SI with mental health status as a moderator. Results 40.8% of respondents reported experiencing insomnia. Both insomnia and number of mental health conditions incrementally increased the risk of SI. However, past-year mental health status was a significant moderator of this relationship, such that for CF personnel with either no (AOR = 1.61, 1.37–1.89) or only one past-year mental health condition (AOR = 1.39, 1.12–1.73), an incremental increase in insomnia was associated with an increased likelihood of SI. However, in personnel with two or more past-year mental health disorders, insomnia was no longer significantly associated with SI (AOR = 1.04, 0.81–1.33). Conclusions Insomnia significantly increased the odds of SI, but only among individuals with no or one mental health condition. Findings highlight the importance of assessing insomnia among CF members in order to further suicide prevention efforts.
... Moreover, sleep disturbance is a core feature of PTSD [6] and a predictor of worse global functionality [7], yet sleep improvement is typically elusive after completion of PTSD-specific behavioral therapies [8,9]. While SSRI and other medication prescriptions are common, the overall evidence for the efficacy of psychopharmacological agents for individuals with PTSD is generally considered to be modest at best [1,10]. Editorialists have affirmed that "New innovative and engaging approaches for the treatment of PTSD are needed" [11]. ...
Article
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Background The objective of this pilot study was to explore the use of a closed-loop, allostatic, acoustic stimulation neurotechnology for individuals with self-reported symptoms of post-traumatic stress, as a potential means to impact symptomatology, temporal lobe high frequency asymmetry, heart rate variability (HRV), and baroreflex sensitivity (BRS). Methods From a cohort of individuals participating in a naturalistic study to evaluate use of allostatic neurotechnology for diverse clinical conditions, a subset was identified who reported high scores on the Posttraumatic Stress Disorder Checklist (PCL). The intervention entailed a series of sessions wherein brain electrical activity was monitored noninvasively at high spectral resolutions, with software algorithms translating selected brain frequencies into acoustic stimuli (audible tones) that were delivered back to the user in real time, to support auto-calibration of neural oscillations. Participants completed symptom inventories before and after the intervention, and a subset underwent short-term blood pressure recordings for HRV and BRS. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and for the last four sessions. Results Nineteen individuals (mean age 47, 11 women) were enrolled, and the majority also reported symptom scores that exceeded inventory thresholds for depression. They undertook a median of 16 sessions over 16.5 days, and 18 completed the number of sessions recommended. After the intervention, 89% of the completers reported clinically significant decreases in post-traumatic stress symptoms, indicated by a change of at least 10 points on the PCL. At a group level, individuals with either rightward (n = 7) or leftward (n = 7) dominant baseline asymmetry in temporal lobe high frequency (23–36 Hz) activity demonstrated statistically significant reductions in their asymmetry scores over the course of their first four sessions. For 12 individuals who underwent short-term blood pressure recordings, there were statistically significant increases in HRV in the time domain and BRS (Sequence Up). There were no adverse events. Conclusion Closed-loop, allostatic neurotechnology for auto-calibration of neural oscillations appears promising as an innovative therapeutic strategy for individuals with symptoms of post-traumatic stress. Trials registration ClinicalTrials.gov #NCT02709369, retrospectively registered on March 4, 2016.
... Overall use seemed to be tailored to treatment of specific symptoms (e.g., insomnia, anxiety, nightmares, and flashbacks) rather than the PTSD itself. Regarding antidepressants, multisite randomized clinical trials have noted some levels of efficacy of selective serotonin reuptake inhibitors (SSRIs), particularly sertraline (36) and escitalopram (37), and serotoninnorepinephrine reuptake inhibitors (SNRIs), particularly venlafaxine, for PTSD treatment (32)(33)(34)(35). However, only 59% of those diagnosed with PTSD may respond to SSRIs (38). ...
Article
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In post-traumatic stress disorder (PTSD) clients, the use of drugs and alcohol may be used as a self-prescribed treatment to both avoid trauma reminders and cope with the related distress. Conversely , substance misuse 'per sé' might predis-pose to experience traumatic events. The present study aimed here at presenting an overview of most recent studies covering a range of issues relating to PTSD and substance misuse; namely: substances most frequently ingested by PTSD clients; neurobiological correlates; and treat-ment/management of these clients. Beyond the alcohol abuse/misuse, drugs most frequently misused are represented by opiates/opioids; sedatives ; cannabis; and cocaine. PTSD-related khat misuse issues are here briefly discussed as well. From the neurobiological point of view, issues relating to amygdala and hippocampus dysfunction, with consequent altered levels of fear extinc-tion/memory disruption, have been considered. Furthermore, PTSD may be characterized by imbalance of a range of neurotransmitter pathways, mainly cannabinoid-receptor (CB1); serotonin; and oxytocin. Although there is currently no effective pharmacotherapy for PTSD, most clients may be regularly prescribed with antidepres-sants; anxiolytics/sedative-hypnotics; and an-tipsychotics. Due to the heterogeneity of PTSD phenotype, focusing on the symptoms/signs of the PTSD client would allow for more personal-ized treatment. Although more research is needed , the development of chemoprophylactic treatments , e.g., intervening pharmacologically after trauma to prevent the occurrence of PTSD seems particularly promising.
... Clinically, these findings might suggest that treatment of comorbid PTSD-MDD should include components specifically addressing each pathology. Indeed, the above-cited research suggested to incorporate specific evidence-based treatment components for MDD into extant PTSD protocols to enhance treatment outcomes (Gros et al., 2010), as PTSD-MDD patients, compared to patients with PTSD alone, exhibit poorer treatment response following PTSD-focused treatment (Bernardy and Friedman, 2015), necessitating novel treatment strategies for PTSD-MDD (Flory and Yehuda, 2015). ...
Article
Background Despite extensive research, symptom structure of posttraumatic stress disorder (PTSD) is highly debated. The network approach to psychopathology offers a novel method for understanding and conceptualizing PTSD. However, extant studies have mainly used small samples and self-report measures among sub-clinical populations, while also overlooking co-morbid depressive symptoms. Methods PTSD symptom network topology was estimated in a sample of 1489 treatment-seeking veteran patients based on a clinician-rated PTSD measure. Next, clinician-rated depressive symptoms were incorporated into the network to assess their influence on PTSD network structure. The PTSD-symptom network was then contrasted with the network of 306 trauma-exposed (TE) treatment-seeking patients not meeting full criteria for PTSD to assess corresponding network differences. Finally, a directed acyclic graph (DAG) was computed to estimate potential directionality among symptoms, including depressive symptoms and daily functioning. Results The PTSD symptom network evidenced robust reliability. Flashbacks and getting emotionally upset by trauma reminders emerged as the most central nodes in the PTSD network, regardless of the inclusion of depressive symptoms. Distinct clustering emerged for PTSD and depressive symptoms within the comorbidity network. DAG analysis suggested a key triggering role for re-experiencing symptoms. Network topology in the PTSD sample was significantly distinct from that of the TE sample. Conclusions Flashbacks and psychological reactions to trauma reminders, along with their strong connections to other re-experiencing symptoms, have a pivotal role in the clinical presentation of combat-related PTSD among veterans. Depressive and posttraumatic symptoms constitute two separate diagnostic entities, but with meaningful between-disorder connections, suggesting two mutually-influential systems.
... In den letzten Jahren wurde unterschiedlichen Theorien folgend eine Vielzahl von Substanzen auf ihre potentielle Wirksamkeit untersucht [77,78]. Dabei konnten die Substanzen Trazodon, Quetiapin, Mirtazapin, Gabapentin, Desipramin, Prazosin, Alprazolam, Clonazepam, Nefazodon, Brofaromin, Bupropion, Citalopram, Divalproex, Risperidon, Tiagabin, Topiramat jedoch keine überzeugende Wirksamkeit in kontrollierten Studien zeigen [62,63,79,80]. ...
Chapter
Die Versorgung von Menschen mit posttraumatischen Belastungsstörungen (PTBS) hat sich in Deutschland ebenso wie die diesbezügliche Forschung in den letzten Jahren beträchtlich weiterentwickelt. Gleichwohl besteht weiter Entwicklungsbedarf zur Verminderung persönlichen Leids und der hohen mit traumatischen Erkrankungen verbundenen Kosten: „Die Trauma-assoziierten Gesundheitskosten allein bewegen sich in einer Größenordnung zwischen 524.5 Mill. Euro und 3.3 Mrd. Euro jährlich. Die Ergebnisse sind als konservativ einzuschätzen, da die Herangehensweise eine Überschätzung der Kosten konsequent versucht zu vermeiden“ [303]. Dieses Kapitel verfolgt das Ziel, einen Überblick über die gegenwärtige Versorgungslandschaft in Deutschland zu geben. Dabei liegt der Schwerpunkt auf der Versorgung Erwachsener. Besonderheiten der Versorgung von Kindern und Jugendlichen werden nur ausnahmsweise thematisiert. Das Kapitel wurde nicht formal konsentiert, sondern bezieht sich auf die persönliche Expertise und den jeweiligen Erfahrungshintergrund der Autorinnen und Autoren. Leitende Fragen bei der Erstellung waren, welche Versorgungsmodelle und -strukturen im Sinne einer evidenzbasierten Behandlung der PTBS hilfreich und inwieweit sie in unserem Versorgungssystem vorhanden sind, aber auch welche Hemmnisse einer (evidenzbasierten) Versorgung entgegenstehen und wie die Versorgung strukturell verbessert werden könnte. Zur Klärung dieser Leitfragen wurden Informationen durch Sichtung der Literatur sowie Expertenbefragungen gesammelt.
... MDD also demonstrates high rates of comorbidity with PTSD; approximately half of individuals with PTSD are diagnosed with concurrent MDD (Flory & Yehuda, 2015), and this comorbidity is associated with greater symptom severity and overall distress, lower levels of functioning, and higher suicide risk than uni-morbid PTSD (Shalev et al., 1998;Flory & Yehuda, 2015). In clinical settings, individuals with comorbid MDD-PTSD evidence poorer treatment prognosis and higher risk of dropout (Flory & Yehuda, 2015;Bernardy & Friedman, 2015). ...
Article
Despite support for the role of self-medication alcohol use in the etiology and maintenance of comorbid posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), theoretical and empirical models of PTSD-AUD rarely account for the role of common comorbidities in risk processes, such as major depressive disorder (MDD). The current study examined the main and interactive effects of PTSD and depressive symptoms on patterns of trauma and alcohol cue reactivity to elucidate potential influences of depression on conditioned craving responses to trauma memories. It was hypothesized that depressive symptoms would be associated with greater cue reactivity (i.e., craving and salivation) to personalized trauma cues, above and beyond the influence of PTSD symptoms. Participants were 184 trauma-exposed young adults (50% female) endorsing current weekly alcohol use. Patterns of craving and salivation were assessed in response to four combinations of narrative (trauma vs. neutral) and beverage (alcohol vs. water) cues. Forward-fitted linear mixed effects models with deviance testing were conducted to ascertain the impact of the within-subjects factors (narrative and beverage cues) and covariates (PTSD and depressive symptoms) on self-reported and physiological (salivation) alcohol craving. Depressive symptoms were associated with elevated drinking coping motives, AUD symptom severity, and alcohol use problems at baseline; however, depressive symptoms did not show main or interactive effects with narrative or beverage cues to predict craving or salivation, p’s > .05. Results suggest that, in the context of PTSD symptoms, depressive symptoms may not exacerbate alcohol craving responses to trauma reminders or alcohol cues.
... 19,20 The pharmacotherapies are also widely used in PTSD treatment. 21 Three selective serotonin reuptake inhibitors (Sertraline, Paroxetine and Fluoxetine) and one serotonin norepinephrine reuptake inhibitor (Venlafaxine) are recommended as monotherapy for the management of PTSD with relatively sufficient evidence. 22e24 Despite empirical support for the above therapies, both psychotherapies and pharmacotherapies are restricted to some limitations. ...
Article
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Purpose Posttraumatic stress disorder (PTSD) is a significant global mental health concern, especially in the military. This study aimed to estimate the efficacy of mindfulness meditation in the treatment of military-related PTSD, by synthesizing evidences from randomized controlled trials. Methods Five electronic databases (Pubmed, EBSCO Medline, Embase, PsychINFO and Cochrane Library) were searched for randomized controlled trials focusing on the treatment effect of mindfulness meditation on military-related PTSD. Information about study characteristics, participant characteristics, intervention details, PTSD outcomes, as well as potential adverse effects was extracted from the included studies. Risk of bias of all the included studies was critically assessed using the Cochrane Collaboration’s tool. R Statistical software was performed for data analysis. Results A total of 1899 records were initially identified and screened. Finally, 19 articles in English language with 1326 participants were included through strict inclusion and exclusion criteria. The results revealed that mindfulness meditation had a significantly larger effect on alleviating military-related PTSD symptoms compared with control conditions, such as treatment as usual, present-centered group therapy and PTSD health education (standardized mean difference = -0.33; 95% CI, -0.45, -0.21; p < 0.0001). Mindfulness interventions with different control conditions (active or non-active control), formats of delivery (group-based or individual-based) and intervention durations (short-term or standard duration) were equally effective in improving military-related PTSD symptoms. Conclusion Findings from this meta-analysis consolidate the efficacy and feasibility of mindfulness meditation in the treatment of military-related PTSD. Further evidences with higher quality and more rigorous design are needed in the future.
... The essential conditions to develop PTSD can be summarized as follows (Bernardy and Friedman 2015): ...
Chapter
Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.
... In den letzten Jahren wurde unterschiedlichen Theorien folgend eine Vielzahl von Substanzen auf ihre potentielle Wirksamkeit untersucht (67,68 (75). Aktuell befinden sich deshalb weitere Studien zu spezifischen psychopharmakologischen Strategien in Arbeit, die die individuelle Pathophysiologie und den richtigen Zeitpunkt eines eventuellen Medikationseinsatzes berücksichtigen (76). ...
Book
Die S3-Leitlinie „Posttraumatische Belastungsstörung“ (PTBS) wurde in ihrer aktualisierten Version von 2019 von zahlreichen Fachgesellschaften unter der Federführung der Deutschsprachigen Gesellschaft für Psychotraumatologie (DeGPT) erarbeitet. Sie enthält gegenüber der Vorversion verschiedene Neuerungen: Aufgrund der Einführung der Diagnose „Komplexe PTBS“ in ICD-11 widmet sich ein neues Kapitel der Behandlung dieser Störung. Auch den neuen Befunden zur Behandlung der PTBS bei Betroffenen mit anderen psychischen Diagnosen wird in einem eigenen Kapitel Rechnung getragen. Darüber hinaus wurde ein eigener Teil der Leitlinie zur „Diagnostik und Behandlung der Posttraumatischen Belastungsstörung bei Kindern- und Jugendlichen“ aufgenommen, der auf spezifische Fragestellungen bei der Behandlung von Kindern und Jugendlichen eingeht. Die S3-Leitlinie „Posttraumatische Belastungsstörung“ ist damit noch umfassender geworden und gibt allen Berufsgruppen Empfehlungen an die Hand, die in die Betreuung von Patienten mit Posttraumatischen Belastungsstörungen eingebunden sind. Die Herausgeber Ursula Gast, Mittelangeln Arne Hofmann, Bergisch Gladbach Christine Knaevelsrud, Berlin Astrid Lampe, Innsbruck Peter Liebermann, Leverkusen Annett Lotzin, Hamburg Andreas Maercker, Zürich Rita Rosner, Eichstätt Ingo Schäfer, Hamburg (Leitlinienkoordinator) Wolfgang Wöller, Bonn Unter der Federführung der Deutschsprachigen Gesellschaft für Psychotraumatologie (DeGPT)
... For example, people who have experienced traumatic events are at a higher risk of acquiring PTSD and they exhibit lower methylation levels at the SLC6A4 locus. Such results contribute to the conjecture that the methylation status of SLC6A4 interacts with brain's processing of the traumatic experiences consequently enhance the risk of developing PTSD [61,62]. ...
Article
Full-text available
Post-traumatic stress disorder (PTSD) is a well-known psychiatric disorder that affects millions of people worldwide. Pharmacodynamic and cognitive-behavioral therapies (CBT) have been used to treat patients with PTSD. However, it remains unclear whether there are concurrent changes in psychopathological and neurophysiological factors associated with PTSD patients. Past reports described those PTSD patients with efficient fatty acid metabolism, neurogenesis, mitochondrial energy balance could improve ability to cope against the conditioned fear responses and traumatic memories. Furthermore, cognitive, behavioral, cellular, and molecular evidence can be combined to create personalized therapies for PTSD sufferers either with or without comorbidities such as depression or memory impairment. Unfortunately, there is still evidence lacking to establish a full understanding of the underlying neurophysiological and psychopathological aspects associated with PTSD. This review has extensively discussed the single nucleotide polymorphism (SNPs) of genetic factors to cause PTSD, the implications of inflammation, neurotransmitter genomics, metabolic alterations, neuroendocrine disturbance (hypothalamus-pituitary-adrenal (HPA) axis), mitochondrial dynamics, neurogenesis, and premature aging related to PTSD-induced psychopathology and neurophysiology. In addition, the review delineated the importance of CBT and several pharmacodynamic therapies to mitigate symptomatology of PTSD.
... The essential conditions to develop PTSD can be summarized as follows (Bernardy and Friedman 2015): ...
... PTSD symptoms are comprised of intrusive thoughts, avoiding reminders, sleep disturbance and increased arousal (American Psychiatric Association, 2013). Although some patients benefit from the available pharmacotherapy, most experience only temporary and limited suppression of their symptoms after treatment (Bernardy and Friedman, 2015;Starke and Stein, 2017). ...
Article
Full-text available
Post-traumatic stress disorder (PTSD) is a mental health condition that is triggered by a stressful event, with symptoms including exaggerated startle response, intrusive traumatic memories and nightmares. The single prolonged stress (SPS) is a multimodal stress protocol that comprises a sequential exposure to physical restraint, forced swimming, predator scent and ether anesthesia. This procedure generates behavioral and neurobiological alterations that resemble clinical findings of PTSD, and thus it is commonly used to model the disease in rodents. Here, we applied c-fos mapping to produce a comprehensive view of stress-activated brain regions in mice exposed to SPS alone or to SPS after oral pretreatment with the serotonin-noradrenaline receptor dual modulator ACH-000029 or the α1-adrenergic blocker prazosin. The SPS protocol evoked c-fos expression in several brain regions that control the stress-anxiety response, including the central and medial amygdala, the bed nucleus of the stria terminalis, the pallidum, the paraventricular hypothalamus, the intermediodorsal, paraventricular and central medial thalamic nuclei, the periaqueductal gray, the lateral habenula and the cuneiform nucleus. These effects were partially blocked by pretreatment with prazosin but completely prevented by ACH-000029. Collectively, these findings contribute to the brain-wide characterization of neural circuits involved in PTSD-related stress responses. Furthermore, the identification of brain areas regulated by ACH-000029 and prazosin revealed regions in which SPS-induced activation may depend on the combined or isolated action of the noradrenergic and serotonergic systems. Finally, the dual regulation of serotonin and α1 receptors by ACH-000029 might represent a potential pharmacotherapy that can be applied in the peri-trauma or early post-trauma period to mitigate the development of symptoms in PTSD patients.
... In den letzten Jahren wurde unterschiedlichen Theorien folgend eine Vielzahl von Substanzen auf ihre potentielle Wirksamkeit untersucht (67,68 (75). Aktuell befinden sich deshalb weitere Studien zu spezifischen psychopharmakologischen Strategien in Arbeit, die die individuelle Pathophysiologie und den richtigen Zeitpunkt eines eventuellen Medikationseinsatzes berücksichtigen (76). ...
Article
Die S3-Leitlinie „Posttraumatische Belastungsstörung“ (PTBS) wurde in ihrer aktualisierten Version von Februar 2019 von zahlreichen Fachgesellschaften unter Federführung der Deutschsprachigen Gesellschaft für Psychotraumatologie (DeGPT) erarbeitet. Sie enthält gegenüber der Vorversion verschiedene Neuerungen. Aufgrund der Einführung der Diagnose „Komplexe PTBS“ in ICD-11 widmet sich ein neues Kapitel der Behandlung dieser Störung. Auch den neuen Befunden zur Behandlung der PTBS bei Betroffenen mit anderen psychischen Diagnosen wird in einem eigenen Kapitel Rechnung getragen. Darüber hinaus wurde ein eigener Teil der Leitlinie zur „Diagnostik und Behandlung der Posttraumatischen Belastungsstörung bei Kindern- und Jugendlichen“ aufgenommen, der auf spezifische Fragestellungen bei der Behandlung von Kindern und Jugendlichen eingeht. Die S3-Leitlinie „Posttraumatische Belastungsstörung“ ist damit noch umfassender geworden und gibt allen Berufsgruppen Empfehlungen an die Hand, die in die Betreuung von Patienten mit posttraumatischen Belastungsstörungen eingebunden sind.
... 146 Given the current lack of treatment options for PTSD and major depression, possibilities of new therapeutic approaches using pharmacological and non-pharmacological interventions that have anti infl ammatory effects may be appropriate. 147, 148 Despite the growing attention given to the infl ammatory patho biology of PTSD, a great deal remains to be clarifi ed, including more detailed mechanisms of infl ammation, the potential usefulness of inflammatory markers as diagnostic/prognostic aides, and efficacy of novel treat ment strategies targeting infl ammation. 146,149 The promise of systems biology, big data, and precision medicine in mental health Precision medicine takes into account the specifi c charac teristics of a patient to personalize prevention, diagnosis, and treatment. ...
Article
Mental health is increasingly being recognized as both a leading cause of disability worldwide and an important area of opportunity for biological breakthroughs. A major limitation in the current diagnosis and management of severe psychiatric conditions is the exclusive reliance on subjective clinical information in the absence of available laboratory tests. A lack of objective biomarkers that reliably identify mental health disorders, and which could serve as targets for diagnosis, treatment response monitoring, and the development of novel therapeutics, remains a fundamental challenge of psychiatry today. Although clinical tests are well established in other areas of medicine, their development in psychiatry has been relatively slow. So far, no biomarkers or other risk markers are available to create profiles to enhance prediction and therapeutic selection in psychiatry. As novel ‘omics-based technologies – such as genomics, proteomics, and metabolomics – and advanced imaging modalities enable researchers to probe the molecular to systemic underpinnings of various disorders, opportunities arise to explore the biological basis for mental health and disease. It is anticipated that specific alterations in blood-based molecular biomarkers, such as DNA, RNA, protein, and metabolite levels, will lead to standardized tests to facilitate diagnosis as they reflect the underlying etiology and mechanisms of disease. They may also pave the way for earlier and more effective treatment and monitoring of patients. Ultimately, the coordinated effort of relevant civilian and military stakeholders – including researchers, physicians and funders – together with standardization initiatives, will be vital to overcoming existing challenges to advance personalized mental health care using sensitive and specific biomarkers.
... TSSB tanısı alan olguların yaklaşık yarısının eş zamanlı olarak Majör Depresif Bozukluk tanısı aldığı bilinmektedir (16). Bununla birlikte Bernardy ve Friedman yalnızca TSSB'si olan hastaların, TSSB ve majör depresif bozukluk komorbiditesi olan hastalara oranla farmakolojik tedaviye yanıt verme oranlarının azaldığını bildirmişlerdir (17). Ayrıca Hoskins ve arkadaşlarının yayınladığı metaanalize göre farmakolojik ajanlar TSSB tedavisinde düşük etki büyüklüğüne sahiptirler (18). ...
Article
Post-traumatic stress disorder (PTSD) has become a major psychiatric and neurological issue. Resveratrol is shown to be effective on depression and anxiety. However, the mechanism of anti-PTSD-like effects of resveratrol remains unknown. The present study aimed to explore the possible molecular and cellular mechanisms underlying the anti-PTSD-like effects of resveratrol. Following a 2-day exposure to inescapable electric foot shocks, animals were administered resveratrol (10, 20, and 40mg/kg, i.g.) during the behavioral tests, which included contextual freezing measurement, elevated plus maze test, staircase test, and open field test. Similar to the positive control drug sertraline (15mg/kg, i.g.), the behavioral deficits of stressed mice were blocked by resveratrol (20 and 40mg/kg, i.g.), which reversed the increased freezing time in contextual freezing measurement and the number of rears in the staircase test and blocked the decrease in time and number of entries in open arms in the elevated plus maze test without affecting the locomotor activity in the open field test. In addition, resveratrol (20 and 40mg/kg, i.g.) antagonized the decrease in the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus. Furthermore, long-term resveratrol attenuated the dysfunctions of hypothalamic-pituitary-adrenal axis simultaneously. Collectively, the evidence indicated that the anti-PTSD-like effects of resveratrol were associated with the normalization of biosynthesis of neurosteroids in the brain and prevention of the hypothalamic-pituitary-adrenal axis dysfunction.
Article
Posttraumatic stress disorder (PTSD) has been conceptualized as an inability to cope with overwhelming stress that is followed by a distinctive pattern of symptoms. This concept has made it possible to develop therapeutic approaches for PTSD that include medication and psychotherapy options. In this article we summarize research studies on pharmacotherapies for PTSD and review new findings in the neurobiology of PTSD that are promoting the development of targeted treatment options. Research findings that have improved our understanding of psychobiological abnormalities associated with PTSD offer clinicians improved treatment strategies. We review those findings, the developments in the medication management of PTSD and common co-occurring disorders, and new areas of pharmacological research on PTSD treatment.
Article
Post-traumatic stress disorder (PTSD) is a highly debilitating stress and anxiety-related disorder that occurs in response to specific trauma or abuse. Genetic risk factors may account for up to 30-40% of the heritability of PTSD. Understanding the gene pathways that are associated with PTSD, and how those genes interact with the fear and stress circuitry to mediate risk and resilience for PTSD will enable the development of targeted therapies to prevent the occurrence of or decrease the severity of this complex multi-gene disorder. This review will summarize recent research on genetic approaches to understanding PTSD risk and resilience in human populations, including candidate genes and their epigenetic modifications, genome-wide association studies and neural imaging genetics approaches. Despite challenges faced within this field of study such as inconsistent results and replications, genetic approaches still offer exciting opportunities for the identification and development of novel therapeutic targets and therapies in the future.
Article
The second article in the series of three for the journal on “PTSD in Court” especially concerns the biological bases that have been found to be associated with PTSD (posttraumatic stress disorder). The cohering concepts in this section relate to risk factors; candidate genes; polygenetics; “gene × environment” interactions; epigenetics; endophenotypes; biomarkers; and connective networks both structurally and functionally (in terms of intrinsic connectivity networks, ICNs, including the DMN, SN, and CEN; that is, default mode, salience, and central executive networks, respectively). Risk factors related to PTSD include pre-event, event- and post-event ones. Some of the genes related to PTSD include: FKBP5, 5-HTTLPR, and COMT (which are, respectively, FK506-binding protein 5 gene, serotonin-transporter linked polymorphic region, catechol-O-methyl-transferase). These genetic findings give an estimate of 30% for the genetic influence on PTSD. The typical brain regions involved in PTSD include the amygdala, hippocampus, and prefrontal cortex, along with the insula. Causal models of behavior are multifactorial and biopsychosocial, and these types of models apply to PTSD, as well. The paper presents a multilevel systems model of psychopathology, including PTSD, which involves three levels — a top-down psychological construct one, a bottom-up symptom connection one, and a middle one involving symptom appraisal. Legally, causality refers to the event at issue needing to meet the bar of being materially contributory to the outcome. Finally, this section of the article reviews empirically-supported therapies for PTSD and the dangers of not receiving treatment for it.
Article
N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28 days after fear conditioning. We found that MK-801 (0.05 and 0.1 mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28 days after fear conditioning. Unlike MK-801, Ro25-681 (3 and 10 mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20 mg/kg PEAQX; 3 and 10 mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders.
Article
Background : Interpersonal trauma (IPT) is one of the most commonly reported types of traumatic experiences and has the greatest likelihood of resulting in a diagnosis of posttraumatic stress disorder (PTSD). Relative to other types of trauma, victims of IPT report greater trauma-specific rumination, whereby they focus on negative consequences of the trauma on their life. Theoretical and empirical work suggest trauma-specific rumination leads to elevated posttraumatic stress symptoms (PTSS); however, there has been a dearth of research examining how trauma type may impact this association. Therefore, the current longitudinal study examined how the experience of IPT moderates the relationship between trauma-specific rumination and later PTSS. Method : Participants (N = 204) enrolled in a clinical trial completed self-report measures of trauma experience, trauma-specific rumination, and PTSS at baseline and 1-month follow-up appointments. Results : Results revealed that IPT moderated the relationship between baseline rumination and 1-month trauma symptoms, even after covarying for participant age and sex, treatment condition, negative affect, and number of previously experienced traumas. Further, this moderation effect was specific to the PTSD numbing cluster. Limitations : Major limitations include measurement of PTSS via PCL-C rather than the PCL-5, as well as a limited sample size, precluding moderation analyses of other trauma types. Conclusions : The current study provides novel findings demonstrating specificity of index trauma type in the longitudinal relationship between rumination and PTSS. Future work is needed to examine how IPT impacts the development of pathways between rumination and PTSS.
Article
Post-traumatic stress disorder (PTSD) is a psychopathological response that develops after exposure to an extreme life-threatening traumatic event. Its prevalence ranges from 0.5% to 14.5% worldwide. Due to the complex pathophysiology of PTSD, currently available treatment approaches are associated with high chances of failure, thus further research to identify better pharmacotherapeutic approaches is needed. The traumatic event associated with fear memories plays an important role in the development of PTSD and could be considered as the main culprit. PTSD patient feels frightened in a safe environment as the memories of the traumatic event are revisited. Neurocircuit involving normal processing of fear memories get disturbed in PTSD hence making a fear memory to remain to dominate even after years of trauma. Persistence of fear memories could be explained by acquisition, re-(consolidation) and extinction triad as all of these processes have been widely explored in preclinical as well as clinical studies and set a therapeutic platform for fear memory associated disorders. This review focuses on neurocircuit and pathophysiology of PTSD in context to fear memories and pharmacological targeting of fear memory for the management of PTSD.
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Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.
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Heterocycles, heteroaromatics and spirocyclic entities are ubiquitous components of a wide plethora of synthetic drugs, biologically active natural products, marketed pharmaceuticals and agrochemical targets. Recognizing their high proportion in drugs and rich pharmacological potential, these invaluable structural motifs have garnered significant interest, thus enabling the development of efficient catalytic methodologies providing access to architecturally complex and diverse molecules with high atom-economy and low cost. These chemical processes not only allow the formation of diverse heterocycles but also utilize a range of flexible and easily accessible building units in a single operation to discover diversity-oriented synthetic approaches. Alkynoates are significantly important, diverse and powerful building blocks in organic chemistry due to their unique and inherent properties such as the electronic bias on carbon–carbon triple bonds posed by electron-withdrawing groups or the metallic coordination site provided by carbonyl groups. The present review highlights the comprehensive picture of the utility of alkynoates (2007–2019) for the synthesis of various heterocycles (> 50 types) using transition-metal catalysts (Ru, Rh, Pd, Ir, Ag, Au, Pt, Cu, Mn, Fe) in various forms. The valuable function of versatile alkynoates (bearing multifunctional groups) as simple and useful starting materials is explored, thus cyclizing with an array of coupling partners to deliver a broad range of oxygen-, nitrogen-, sulfur-containing heterocycles alongside fused-, and spiro-heterocyclic compounds. In addition, these examples will also focus the scope and reaction limitations, as well as mechanistic investigations into the synthesis of these heterocycles. The biological significance will also be discussed, citing relevant examples of drug molecules highlighting each class of heterocycles. Graphic Abstract This review summarizes the recent developments in the synthetic methods for the synthesis of various heterocycles using alkynoates as readily available starting materials under transition-metal catalysis.
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Cannabis use is increasing among some demographics in the United States and is tightly linked to anxiety, trauma, and stress reactivity at the epidemiological and biological level. Stress-coping motives are highly cited reasons for cannabis use. However, with increased cannabis use comes the increased susceptibility for cannabis use disorder (CUD). Indeed, CUD is highly comorbid with posttraumatic stress disorder (PTSD). Importantly, endogenous cannabinoid signaling systems play a key role in the regulation of stress reactivity and anxiety regulation, and preclinical data suggest deficiencies in this signaling system could contribute to the development of stress-related psychopathology. Furthermore, endocannabinoid deficiency states, either pre-existing or induced by trauma exposure, could provide explanatory insights into the high rates of comorbid cannabis use in patients with PTSD. Here we review clinical and preclinical literature related to the cannabis use-PTSD comorbidity, the role of endocannabinoids in the regulation of stress reactivity, and potential therapeutic implications of recent work in this area.
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Veterans older than 60 years of age represent the majority of the veteran population. Evaluation and management of common psychiatric conditions in older veterans, including neurocognitive disorders, depression, and post-traumatic stress disorder (PTSD), require special consideration due to the increased frailty, greater medical and psychiatric comorbidity, and unique psychosocial challenges faced by this population. Suicide risk is increased in older veterans, particularly combat veterans and former prisoners of war. This chapter reviews the nature, course, and consequences of common psychiatric disorders in older veterans and suggests future directions for research.
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Cannabis L. belongs to Cannabaceae family known as ‘hemp’ and has been used as a mind-altering drug as described in prehistoric societies of Eurasia and Africa. A total of 100 phytocannabinoids have been reported from Cannabis sativa L. till date, owing to their therapeutic values. The two primary constituents present in Cannabis are non-psychoactive cannabidiol (CBD) and psychoactive Δ9-tetrahydrocannabinol (THC). CBD has enormous potential for the development as a drug candidate as depicted by diverse clinical and preclinical studies for the treatment of various neuropsychiatric disorders, arthritis, cancer and other diseases. Regardless of its therapeutic importance and interaction with the endocannabinoid system (ECS), definite pharmacological mechanism is not clearly established. Apart from medicinal research, there are a number of aspects which should be taken under consideration such as opinion of FDA, legal aspects of cannabis and international scenario during the drug development based on this plant.
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Post-traumatic stress disorder (PTSD) is a complex disorder that involves dysregulation of multiple neurobiological systems. The traumatic stressor plays a causal role in producing psychological dysfunction and the pattern of findings suggests that the hypothalamic–pituitary–adrenal (HPA) axis, which is instrumental for stress adaptation, is critically dysfunctional in PTSD. Given the lack of understanding of the basic mechanisms and underlying pathways that cause the disorder and its heterogeneity, PTSD poses challenges for treatment. Targeting the endocannabinoid (ECB) system to treat mental disorders, and PTSD in particular, has been the focus of research and interest in recent years. The ECB system modulates multiple functions, and drugs enhancing ECB signaling have shown promise as potential therapeutic agents in stress effects and other psychiatric and medical conditions. In this review, we focus on the interaction between the ECB-HPA systems in animal models for PTSD and in patients with PTSD. We summarize evidence supporting the use of cannabinoids in preventing and treating PTSD in preclinical and clinical studies. As the HPA system plays a key role in the mediation of the stress response and the pathophysiology of PTSD, we describe preclinical studies suggesting that enhancing ECB signaling is consistent with decreasing PTSD symptoms and dysfunction of the HPA axis. Overall, we suggest that a pharmacological treatment targeted at one system (e.g., HPA) may not be very effective because of the heterogeneity of the disorder. There are abnormalities across different neurotransmitter systems in the pathophysiology of PTSD and none of these systems function uniformly among all patients with PTSD. Hence, conceptually, enhancing ECB signaling may be a more effective avenue for pharmacological treatment.
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Post-traumatic stress disorder (PTSD) may be a significant mental health concern for pregnant and postpartum women. A number of studies have shown that PTSD can have a negative impact on women, their relationship and birth outcomes. Furthermore, there are as well evidence that it may also affect infant emotion regulation and development. Although there has been extensive amount of research on the correlates of perinatal PTSD, the treatment of PTSD remains still unclear. This chapter presents recommendations for pharmacological treatment as well as the risks of untreated PTSD during the perinatal period for PTSD.
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Ein Trauma ist ein äußeres Ereignis, das bei den Betroffenen das Gefühl einer überwältigenden Bedrohung und Katastrophe vermittelt und Todesangst, Panik, Ohnmacht und Hilflosigkeit auslöst. Eine akute Traumaexposition geht mit einer psychischen und psychosomatischen Erschütterung einher, von der sich aber in der Regel die meisten Menschen innerhalb absehbarer Zeit wieder gut erholen. Bei manchen traumatisierten Personen können in der Folge jedoch zahlreiche psychische Störungen auftreten. Die akute Belastungsstörung (ABS) und die posttraumatische Belastungsstörung (PTBS) stellen prägnanztypische Traumafolgestörungen dar, die sowohl im ICD- als auch im DSM-Klassifikationssystem gesondert thematisiert werden. Für die komplizierte Trauer existiert im DSM-5 kein eigener diagnostischer Status, jedoch wird die ICD-11 die Diagnose einer anhaltenden Trauer führen. Die extremen und meist entwicklungspsychopathologischen Traumatisierungen werden innerhalb des DSM-5 unter der PTBS subsumiert, in der künftigen ICD-11-Revision werden sie hingegen einen eigenständigen diagnostischen Status einnehmen. Die PTBS wird im DSM-5 mit der ABS und den Anpassungsstörungen neu unter den trauma- und stressbezogenen Störungen zusammengefasst. Die ICD-11 wird sich diesbezüglich analog verhalten. Die ABS deckt die ersten vier Wochen nach einer Traumaexposition ab, eine PTBS kann erst nach dieser Zeitspanne diagnostiziert werden. Beide zeichnen sich syndromal durch ein intrusives Wiedererleben der Traumaerfahrung, ein traumabezogenes Vermeidungsverhalten sowie durch eine autonome Hyperaktivität oder aber durch prominente dissoziative Symptome aus. Für eine differenzielle Behandlung existieren empirisch validierte psychotherapeutische und psychopharmakologische Ansätze. Die Verläufe von PTBS sind aber nach wie vor häufig chronisch und behindernd. Darum werden derzeit intensive Forschungsbestrebungen unternommen, um zu günstigeren Therapieoptionen zu gelangen.
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Although cognitive behavioral therapy (CBT) is a generally effective treatment for treating anxiety disorders, there is clearly still room for further improvements. Recent advances in neuroscience of extinction learning led to novel clinical strategies to augment exposure-based treatments with d-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate receptor. This review provides an update on the current knowledge of DCS as an augmentation strategy of CBT for anxiety disorders. The adequacy of the CBT to be augmented, the dose of DCS, and the timing and duration of augmentation efforts all appear to be important moderating variables. Moreover, there is evidence that DCS may also augment fear memory reconsolidation if the fear level remains high after the exposure. Future studies need to examine whether DCS can augment CBT when administered after exposure in order to develop a tailored administration strategy to maximize its clinical utility.
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Importance Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents.Objective To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions.Data Sources Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles.Study Selection Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression.Data Extraction and Synthesis Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.Main Outcomes and Measures Depression scores after treatment and adverse effects.Results Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 4258) and 4 investigated cytokine inhibitors (n = 2004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, −0.34; 95% CI, −0.57 to −0.11; I2 = 90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I2 = 73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.Conclusions and Relevance Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
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Objective: The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma. Method: After an introductory session, five sessions of virtual reality exposure were augmented with D-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD. Results: PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between D-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only. At posttreatment, the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes. Conclusions: A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of D-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.
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Viewing PTSD as a disorder of emotional learning, this study used a cognitive-enhancer synergistically with virtual reality exposure therapy (VRE) for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions, in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at: pretreatment, following sessions 3, 6, 10, posttreatment, and at six-months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at six weeks, with medium to large between-group effect sizes immediately posttreatment and six months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at posttreatment; 69% vs 17% at six-months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared to the VRE-placebo group. These results suggest a promising new treatment for PTSD.Neuropsychopharmacology accepted article preview online, 12 November 2013. doi:10.1038/npp.2013.317.
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This study evaluated the effect of comorbid personality disorders on treatment outcome for male and female Veterans with posttraumatic stress disorder (PTSD). One hundred and sixty-six Veterans participated in a PTSD Residential Rehabilitation Program, which included cognitive processing therapy (CPT) provided in a combined individual and group format. Sixty-six percent of participants met criteria at pre-treatment for at least one personality disorder. No difference was found between participants with and without personality disorders on pre-treatment demographic variables, self-reported PTSD symptoms, or clinician-assessed PTSD symptoms. However, differences were found between the groups on self-reported depression symptoms. When controlling for pre-treatment self-reported depression symptoms, results indicated that both groups had significant reductions on PTSD outcome measures, regardless of the presence of a personality disorder. Additionally, a comparable number of participants with and without personality disorders no longer met criteria for PTSD following treatment. Findings suggest that Veterans with personality disorders can benefit from a CPT-based PTSD residential program.
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Although prolonged exposure therapy (PE) is considered an evidence-based treatment for PTSD, there has been little published about the use of this treatment for older adults with comorbid early-stage dementia. As the number of older adults in the United States continues to grow, so will their unique mental health needs. The present article describes the successful coordination of care and application of PE in the assessment and treatment of a Vietnam veteran with comorbid PTSD and early-stage dementia. Measures related to the patient's cognitive and psychological functioning were obtained before, during, and after treatment. PE was associated with significant declines in PTSD and depression symptoms. Moreover, the patient's cognitive functioning was made clearer in the absence of severe psychiatric symptoms. Factors contributing to the patient's positive response are discussed.
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Alcohol dependence comorbid with posttraumatic stress disorder (PTSD) has been found to be resistant to treatment. In addition, there is a concern that prolonged exposure therapy for PTSD may exacerbate alcohol use. To compare the efficacy of an evidence-based treatment for alcohol dependence (naltrexone) plus an evidence-based treatment for PTSD (prolonged exposure therapy), their combination, and supportive counseling. A single-blind, randomized clinical trial of 165 participants with PTSD and alcohol dependence conducted at the University of Pennsylvania and the Philadelphia Veterans Administration. Participant enrollment began on February 8, 2001, and ended on June 25, 2009. Data collection was completed on August 12, 2010. Participants were randomly assigned to (1) prolonged exposure therapy plus naltrexone (100 mg/d), (2) prolonged exposure therapy plus pill placebo, (3) supportive counseling plus naltrexone (100 mg/d), or (4) supportive counseling plus pill placebo. Prolonged exposure therapy was composed of 12 weekly 90-minute sessions followed by 6 biweekly sessions. All participants received supportive counseling. The Timeline Follow-Back Interview and the PTSD Symptom Severity Interview were used to assess the percentage of days drinking alcohol and PTSD severity, respectively, and the Penn Alcohol Craving Scale was used to assess alcohol craving. Independent evaluations occurred prior to treatment (week 0), at posttreatment (week 24), and at 6 months after treatment discontinuation (week 52). Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, -63.9% [95% CI, -73.6% to -54.2%] for prolonged exposure therapy plus naltrexone; -63.9% [95% CI, -73.9% to -53.8%] for prolonged exposure therapy plus placebo; -69.9% [95% CI, -78.7% to -61.2%] for supportive counseling plus naltrexone; and -61.0% [95% CI, -68.9% to -53.0%] for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases. In this study of patients with alcohol dependence and PTSD, naltrexone treatment resulted in a decrease in the percentage of days drinking. Prolonged exposure therapy was not associated with an exacerbation of alcohol use disorder. clinicaltrials.gov Identifier: NCT00006489.
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The Department of Veterans Affairs (VA) and Department of Defense (DoD) issued a revised posttraumatic stress disorder (PTSD) Clinical Practice Guideline (CPG) in 2010 with specific pharmacotherapy recommendations for evidence-based quality care. The authors examined prescribing frequencies over an 11-year period prior to the release of the new guideline to determine gender differences in pharmacotherapy treatment in veterans with PTSD. National administrative VA data from 1999 to 2009 were used to identify veterans with PTSD using ICD-9 codes extracted from inpatient discharges and outpatient clinic visits. Prescribing of antidepressants, antipsychotics and hypnotics was determined for each year using prescription drug files. Women were more likely than men to receive medication across all classes except prazosin where men had higher prescribing frequency. The proportion of women receiving either of the first-line pharmacotherapy treatments for PTSD, selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI), increased from 56.4 % in 1999 to 65.7 % in 2009, higher rates than seen in men (49.2 % to 58.3 %). Atypical antipsychotic prescriptions increased from 14.6 % to 26.3 % and nonbenzodiazepine hypnotics increased from 3.8 % to 16.9 % for women, higher frequencies than seen in men for both medications (OR = 1.31, 1.43 respectively). The most notable gender discrepancy was observed for benzodiazepines where prescriptions decreased for men (36.7 % in 1999 to 29.8 % in 2009) but steadily increased for women from 33.4 % to 38.3 %. A consistent pattern of increased prescribing of psychotropic medications among women with PTSD was seen compared to men. Prescribing frequency for benzodiazepines showed a marked gender difference with a steady increase for women despite guideline recommendations against use and a decrease for men. Common co-occurring disorders and sleep symptom management are important factors of PTSD pharmacotherapy and may contribute to gender differences seen in prescribing benzodiazepines in women but do not fully explain the apparent disparity.
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Context Despite the high prevalence, chronicity, and associated comorbidity of posttraumatic stress disorder (PTSD) in the community, few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder.Objective To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity.Design Twelve-week, double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo lead-in period, conducted between May 1996 and June 1997.Setting Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers.Patients A total of 187 outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years; 73% were women; and 61.5% experienced physical or sexual assault).Intervention Patients were randomized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or placebo (n=93).Main Outcome Measures Baseline-to-end-point changes in CAPS-2 total severity score, Impact of Event Scale total score (IES), and Clinical Global Impression–Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared by treatment vs placebo groups.Results Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures (mean change from baseline to end point for CAPS-2 total score, −33.0 vs −23.2 [P=.02], and for CGI-S, −1.2 vs −0.8 [P=.01]; mean CGI-I score at end point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing a trend toward significance (mean change from baseline to end point, −16.2 vs −12.1; P=.07). Using a conservative last-observation-carried-forward analysis, treatment with sertraline resulted in a responder rate of 53% at study end point compared with 32% for placebo (P=.008, with responder defined as >30% reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score. Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing (P=.02) and increased arousal (P=.03) but not on reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia the only adverse effect reported significantly more often than placebo (16.0% vs 4.3%; P=.01).Conclusions Our data suggest that sertraline is a safe, well-tolerated, and effective treatment for PTSD. Figures in this Article Traumatic stress is a significant public health problem1 that frequently results in a distinctive pattern of persistent and disabling psychological and physiological symptoms.2- 3 Once thought to be primarily limited to soldiers in combat, posttraumatic stress disorder (PTSD) is now recognized in civilians, including those who have experienced natural disasters, physical and sexual assault, fire, motor vehicle and other serious trauma, as well as those who have witnessed inflicted injury or death. Exposure to a traumatic event is common, estimated in the range of 5% to 35% annually, with a lifetime exposure to 1 or more traumatic events occurring in more than 50% of the US population.1 The clinical presentation of PTSD is characterized by moderate-to-severe symptoms in 3 separate domains: reexperiencing (intrusive thoughts, nightmares, flashbacks, images, or memories), emotional numbing and avoidance (flattened affect or detachment, loss of interest and motivation, and avoidance of any activity, place, person, or topic associated with the trauma); and increased arousal (startle reactions, poor concentration, irritability and jumpiness, insomnia, or hypervigilance). With a minimum symptom duration of 1 month at a level of severity necessary to impair an individual's functioning, PTSD has been estimated to have a lifetime prevalence in the range of 5% to 12%, based on epidemiological surveys,1,4- 5 with women having twice the prevalence rate of men. Frequently, PTSD is a chronic illness, with a median time to recovery in the range of 3 to 5 years.1,6 The disorder is associated with unusually high rates of lifetime psychiatric comorbidity,1,5,7 especially major depression (odds ratio relative to non-PTSD sample, approximately 4-7), alcoholism and drug abuse (odds ratio, approximately 3), and panic disorder (odds ratio in the range of 3-20). Research has shown that previous psychiatric history is a risk factor for development of PTSD following trauma exposure.1,8- 10 Furthermore, patients with PTSD often have subsequent onset of another psychiatric disorder. Analysis of epidemiological data relating to age at time of trauma and onset of PTSD diagnosis suggests that when PTSD occurs in conjunction with a mood or anxiety illness, it constitutes the primary disorder in 41% to 58% of women and 29% to 51% of men.1 The high chronicity, severity, and comorbidity of PTSD are associated with high levels of functional and psychosocial disability,11- 12 as well as increased somatic complaints and health care use.13- 16 An empirical review published in 199217 identified only 5 controlled trials of medication treatment,18- 22 all of which were limited to men (mostly combat veterans). This review found "modest efficacy" for pharmacological and behavioral treatments with "the strongest efficacy favoring behavioral techniques." Only 3 double-blind, placebo-controlled studies have been published since that review. Two reported conflicting results for the never-marketed monoamine oxidase type A inhibitor brofaromine.23- 24 A third study reported positive results for fluoxetine (n=10) compared with placebo (n=13) in a subgroup of civilian patients with PTSD,25 while no significant differences between fluoxetine and placebo were found in a subgroup of patients with combat-related PTSD treated in a Veterans Affairs clinic setting. The selective serotonin reuptake inhibitor antidepressants appear promising in the treatment of PTSD for various reasons. Optimally, a candidate therapy should be well-tolerated and able to effectively treat the core clinical features of PTSD and common affective and anxiety disorder comorbidity, as well as to improve psychosocial functioning. Sertraline, one of the most widely prescribed selective serotonin reuptake inhibitor antidepressants, effectively attenuates the behavioral syndrome that occurs in animals after exposure to uncontrollable stress,26 which has been interpreted as an animal model of PTSD.27- 28 Two small, open-label studies29- 30 have shown efficacy for sertraline, 1 in the treatment of those with PTSD due to sexual assault and 1 in patients with comorbid alcoholism and PTSD. The efficacy of sertraline in treating depression,31- 33 panic disorder,34- 36 and obsessive-compulsive disorder37- 38 are well established. In light of this clinical activity, we conducted a large, placebo-controlled study from May 1996 to June 1997 to examine the efficacy of sertraline in the treatment of PTSD. Because of the marked impairment in occupational, health, and psychosocial functioning associated with PTSD, quality-of-life, psychosocial, and symptomatic outcomes were assessed.7,12
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In patients with co-morbid obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD), repetitive behavior patterns, rituals, and compulsions may ward off anxiety and often function as a coping strategy to control reminders of traumatic events. Therefore, addressing the traumatic event may be crucial for successful treatment of these symptoms. In this case report, we describe a patient with comorbid OCD and PTSD who underwent pharmacotherapy and psychotherapy. Case Report. A 49-year-old Dutch man was treated for severe PTSD and moderately severe OCD resulting from anal rape in his youth by an unknown adult man. The patient was treated with paroxetine (60 mg), followed by nine psychotherapy sessions in which eye movement desensitization and reprocessing (EMDR) and exposure and response prevention (ERP) techniques were applied. During psychotherapy, remission of the PTSD symptoms preceded remission of the OCD symptoms. This study supports the idea of a functional connection between PTSD and OCD. Successfully processing the trauma results in diminished anxiety associated with trauma reminders and subsequently decreases the need for obsessive-compulsive symptoms.
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The current study examined the longitudinal effects of clinical and treatment utilization factors on aggressive behavior among 376 help-seeking U.S. veterans recently diagnosed with posttraumatic stress disorder (PTSD) who were followed for 5-12 months. Participants were sampled from 4 strata: male Iraq/Afghanistan veterans, female Iraq/Afghanistan veterans, male prior-era veterans, and female prior-era veterans. Hierarchical regression analyses indicated that changes in PTSD severity were significantly associated with changes in aggressive behavior among veterans who reported any aggression at baseline (β = .15). Changes in days of alcohol intoxication also were positively associated with changes in aggressive behavior (β = .16). Participants with both a benzodiazepine prescription and any baseline aggression were significantly more likely to increase in aggressive behavior over time (β = .14). Contrary to our hypotheses, reductions in aggressive behavior were not related to the number of outpatient mental health visits or to first-line recommended psychotropic medications. Results inform assessment and clinical research on changes in aggressive behavior among veterans with PTSD.
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Treatment guidelines and reviews of outcome studies agree that drugs are valuable for moderation of irrational moods and impulsivity that interfere with thoughtfulness and cooperativeness. As such, they empower patients to make good use of psychotherapy for mastery of the risk of betrayal in intimate relationships, which is the typical recurrent traumatic event in complex posttraumatic disorders. Psychotherapy, for its part, has demonstrated correction and lasting remission of disorder in the aftermath of certain kinds of single trauma and promises further development to achieve similar efficacy for complex posttraumatic disorders. This article summarizes the strengths and limitations of each class of psychiatric drugs. It explains how the natural course of complex posttraumatic disorders greatly contaminates observations of medication efficacy and fosters unrealistic expectations for drug development.
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In two recent studies conducted by our group, a treatment combining propranolol with a brief reactivation session subsequently reduced posttraumatic stress disorder (PTSD) symptom severity and diagnosis, as well as reducing psychophysiological responses during trauma-related script-driven imagery. One likely explanation for those results is that memory reconsolidation was blocked by propranolol. We explored the influence of various predictors on treatment outcome (i.e., PTSD severity), and whether the treated individuals improved in other important domains of functioning associated with PTSD. Thirty-three patients with longstanding PTSD participated in a 6-week open-label trial consisting of actively recalling one's trauma under the influence of propranolol, once a week. Treated patients reported a better quality of life, less comorbid depressive symptoms, less negative emotions in their daily life and during trauma recollections. Women were also found to improve more than men. Type of trauma (childhood vs. adulthood), time elapsed since trauma, borderline personality traits, depressive symptoms severity, Axis I comorbidity, and age did not influence treatment outcome. These results must await publication of a randomized-controlled trial to further delineate effectiveness with this novel treatment approach.
Article
Context No large-scale posttraumatic stress disorder drug trials have been conducted to evaluate treatment effects beyond 12 weeks outside of those with selective serotonin reuptake inhibitors. Objective To evaluate the efficacy of venlafaxine extended release (ER), a serotonin norepinephrine reuptake inhibitor, in posttraumatic stress disorder. Design 6-month, double-blind, placebo-controlled trial. Setting International study at 56 sites. Patients Adult outpatients (N = 329) with a primary diagnosis of posttraumatic stress disorder as defined in the DSM-IV, symptoms for 6 months or longer, and a 17-item Clinician-Administered Posttraumatic Stress Disorder Scale score of 60 or higher. Intervention Patients randomly assigned to receive flexible doses of venlafaxine ER (37.5-300 mg/d) or placebo for 24 weeks. Main Outcome Measures Primary measure was the change from baseline in the Clinician-Administered Posttraumatic Stress Disorder Scale score. Secondary measures included remission, defined as a Clinician-Administered Posttraumatic Stress Disorder Scale score of 20 or lower, and changes in symptom cluster scores, frequency of remission, and time to remission. Measures of stress vulnerability, resilience, depression, quality of life, functioning, and global illness severity were also taken. Results Mean changes from baseline in Clinician-Administered Posttraumatic Stress Disorder Scale total scores at end point were –51.7 for venlafaxine ER and –43.9 for placebo (P = .006). Improvement was significantly greater for the venlafaxine ER group than for the placebo group in cluster scores for reexperiencing (P = .008) and avoidance/numbing (P = .006), but not for hyperarousal. Remission rates were 50.9% for venlafaxine ER and 37.5% for placebo (P = .01). The venlafaxine ER group also showed significantly greater improvement at end point than the placebo group (P<.05) on all other reported outcome measures. The mean maximum daily dose of venlafaxine ER was 221.5 mg/d. Withdrawal rates were similar between groups with no significant difference in dropouts attributable to adverse events. Conclusion In this study, venlafaxine ER was effective and well tolerated in short-term and continuation treatment of patients with posttraumatic stress disorder.
Article
Background Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse. Aims To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse. Method This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse. Results Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups. Conclusions Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.
Article
Background: Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated lifetime prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode.Methods: Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey.Results: The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years.Conclusions: Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.
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Objective: The goal of the current study was to characterize the quality of life (QOL) and functional impairment associated with posttraumatic stress disorder (PTSD) and to report the QOL/functional response over the course of long-term treatment. Method: QOL and psychosocial functioning were analyzed in 359 randomly assigned patients across a 3-phase study of sertraline in the treatment of chronic DSM-III-R-defined PTSD: (1) 12 weeks of double-blind, placebo-controlled acute treatment with sertraline in flexible doses of 50 to 200 mg/day, (2) 24 weeks of open-label continuation treatment with sertraline among all study completers (regardless of initial study drug assignment or endpoint responder status), and (3) 28 weeks of double-blind, placebo-controlled maintenance treatment with sertraline in continuation phase responders. Assessments included the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), emotional role functioning and mental health subscales of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), as well as the occupational and social functioning items on the Clinician-Administered PTSD Scale, Part 2 (CAPS-2). Results: At acute phase baseline, QOL was significantly impaired as reflected by a mean Q-LES-Q score of 56% of the total possible score and a CAPS-2 social/occupational impairment composite score of 4.4. Sertraline treatment was associated with marked improvement on all QOL/functional measurements: at the end of the acute treatment phase, 58% of responders on treatment with sertraline had achieved Q-LES-Q total scores within 10% of community norms. Twenty-four weeks of continuation treatment led to an additional 20% improvement in QOL and measures of functioning. Double-blind discontinuation of sertraline resulted in recurrence of PTSD symptoms and a worsening of QOL and functional measures, although the degree of exacerbation in symptomatology and psychosocial impairment was notably less than at study entry. Conclusion: Sertraline treatment of chronic PTSD is associated with rapid improvement in quality of life that is progressive and sustained over the course of more than 1 year of treatment.
Article
BACKGROUND: The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. METHODS: Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). RESULTS: Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. CONCLUSIONS: These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.
Article
Background The course of posttraumatic stress disorder (PTSD) is frequently and severely complicated by co-occurring alcohol use disorder (AUD), yet there are few reports of pharmacologic treatments for these comorbid conditions. The objective of this pilot study was to obtain a preliminary assessment of the efficacy and safety of topiramate in reducing alcohol use and PTSD symptoms in veterans with both disorders.Methods This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot trial of flexible-dose topiramate up to 300 mg/d in 30 veterans with PTSD and AUD. The primary outcome measure was frequency of drinking. Secondary outcomes consisted of other measures of alcohol use and PTSD symptom severity.ResultsWithin-group analyses showed that topiramate treatment was associated with significant reductions in frequency and amount of alcohol use and alcohol craving from baseline through week 12. Between-group analyses showed that topiramate reduced frequency of alcohol use and alcohol craving significantly more than placebo and tended to reduce drinking amount. Topiramate treatment was also associated with decreased PTSD symptom severity and tended to reduce hyperarousal symptoms compared with placebo. Topiramate transiently impaired learning and memory, with significant recovery by the end of treatment.Conclusions These preliminary results indicate that in veterans with co-occurring PTSD and AUD, topiramate may be effective in reducing alcohol consumption, alcohol craving, and PTSD symptom severity—particularly hyperarousal symptoms. Topiramate was associated with transient cognitive impairment but was otherwise well tolerated.
Article
Importance: Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. Objective: To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. Design, setting, and participants: Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements. Interventions: Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). Main outcomes and measures: The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. Results: Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. Conclusions and relevance: This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. Trial registration: clinicaltrials.gov Identifier: NCT00749203.
Article
Posttraumatic stress disorder (PTSD) is a chronic disabling illness, resulting from exposure to extreme traumatic event. Although different pharmacologic agents are suggested for treatment of PTSD, none have been completely effective in eliminating symptoms. The purpose of this study was to assess the use of baclofen as an add-on to citalopram in treatment of PTSD. In this double-blind clinical trial, 40 Iranian combat veterans with PTSD were randomly assigned to 2 groups. The first group received a combination treatment of 20 to 60 mg/d citalopram and 40 mg/d baclofen, and the second group received 20 to 60 mg/d citalopram plus placebo. Symptom severity was assessed by Clinician-Administered PTSD Scale at the beginning of the study and after 2, 4, 6, and 8 weeks. Global Assessment of Functioning and Hamilton Rating Scale for Anxiety and Depression were also used at the same periods. Data were analyzed with independent t test and paired t test using SPSS software version 13 (IBM, Armonk, NY). Twenty-three male patients (baclofen group, 13 patients; placebo group, 10 patients) completed the study. Dropout from the treatment was not caused by adverse effects of the new medications in any of the subjects. Baclofen group showed significantly larger improvement in Clinician-Administered PTSD Scale total (P = 0.040), hyperarousal (P = 0.020), and avoidance (0.020) scores, Global Assessment of Functioning score (0.001), depression (P = 0.000), and anxiety (P = 0.000) after 8 weeks of treatment. No intergroup difference was found in improvement of reexperience symptoms (P = 0.740). Baclofen showed to be an effective add-on to selective serotonin reuptake inhibitors in treatment of PTSD for better symptom recovery and functional improvement.
Article
The necessity of specific intervention components for the successful treatment of patients with posttraumatic stress disorder is the subject of controversy. To investigate the complexity of clinical problems as a moderator of relative effects between specific and nonspecific psychological interventions. We included 18 randomized controlled trials, directly comparing specific and nonspecific psychological interventions. We conducted moderator analyses, including the complexity of clinical problems as predictor. Our results have confirmed the moderate superiority of specific over nonspecific psychological interventions; however, the superiority was small in studies with complex clinical problems and large in studies with noncomplex clinical problems. For patients with complex clinical problems, our results suggest that particular nonspecific psychological interventions may be offered as an alternative to specific psychological interventions. In contrast, for patients with noncomplex clinical problems, specific psychological interventions are the best treatment option.
Article
In 2010, the World Health Organization (WHO) launched the Mental Health Gap Action Program (mhGAP) Intervention Guide for nonspecialized health settings (ie, for general health staff in first- and second-level health facilities, including primary care and district hospital settings) to address the wide treatment gap for mental disorders in low- and middle-income countries.¹- 3 Several priority mental disorders, including depression and substance use, have been addressed in previous mhGAP modules and related guidelines.¹,3
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Objective: The authors conducted a 15-week randomized controlled trial of the alpha-1 adrenoreceptor antagonist prazosin for combat trauma nightmares, sleep quality, global function, and overall symptoms in active-duty soldiers with posttraumatic stress disorder (PTSD) returned from combat deployments to Iraq and Afghanistan. Method: Sixty-seven soldiers were randomly assigned to treatment with prazosin or placebo for 15 weeks. Drug was titrated based on nightmare response over 6 weeks to a possible maximum dose of 5 mg midmorning and 20 mg at bedtime for men and 2 mg midmorning and 10 mg at bedtime for women. Mean achieved bedtime doses were 15.6 mg of prazosin (SD=6.0) and 18.8 mg of placebo (SD=3.3) for men and 7.0 mg of prazosin (SD=3.5) and 10.0 mg of placebo (SD=0.0) for women. Mean achieved midmorning doses were 4.0 mg of prazosin (SD=1.4) and 4.8 mg of placebo (SD=0.8) for men and 1.7 mg of prazosin (SD=0.5) and 2.0 mg of placebo (SD=0.0) mg for women. Primary o