Original Research Timing of Oseltamivir Administration and Outcomes in Hospitalized Adults With Pandemic 2009 Infl uenza A(H1N1) Virus Infection Diego Viasus , MD ; José Ramón Paño-Pardo , MD , PhD ; Jerónimo Pachón , MD , PhD ; Melchor Riera , MD , PhD ; Francisco López-Medrano , MD , PhD ; Antoni Payeras , MD , PhD ; M. Carmen Fariñas , MD , PhD ; Asunción Moreno , MD , PhD ; Jesús Rodríguez-Baño , MD , PhD ; José Antonio Oteo , MD , PhD ; Lucia Ortega , MD , PhD ; Julián Torre-Cisneros , MD , PhD ; Ferrán Segura , MD , PhD ; and Jordi Carratalà , MD , PhD ; for the Novel Infl uenza A(H1N1) Study Group of the Spanish Network for Research in Infectious Diseases (REIPI) *
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PtsdDr Taryn Cowain Clinical Director RGH Ward 17
Long known about psychological effects of Post trauma reactions documented as far back In 1915 a clear account of PTSD described in The Lancet by Dr Forsyth. Experience of re-experiencing, reliving, arousal
Defence of Rorke's Drift
1RAR 1960. At end of Malayan Emergency
The problem – In The USA 2000 - 2009: USA Department of Defence
767,290 diagnosed with a psychiatric condition 344,288 diagnosed in more than one category Incidence of PTSD increased 6-fold, 2003-2008 Psychiatric disorders - leading cause of hospitalization for men in U.S. military Conditions of Interest Adjustment disorder Alcohol or substance abuse Anxiety disorders Personality disorders Active Combat Troops: 2007-2010 US Military Actively deployed troops who had ever been diagnosed with a mental health disorder: major depression bipolar disorder alcohol dependence substance dependence USA - Medical Discharge 2002: 50% of service members hospitalized for a psychiatric condition medical y discharged within 6 Only 12% of service members hospitalized for other conditions discharged In the ADF its probably much higher. USA Medical Discharge 2003-2008, percentage of medical discharges related to a psychiatric condition: Army 22% Navy 24% Marine Corps 42% Post Discharge - USA 222,000 Iraq veterans: 35% sought psychiatric treatment in the year after returning home -> Veteran's Affairs Data Mental Health Epidemiology in Dohrenwend O'Toole 1996 – 2006 Lifetime
ADF Vietnam veterans PTSD life time ADF Gulf War Veterans, 10–15 years after Gulf War (1990), 5.4% of 1871 have current Royal Australian Navy (RAN) estimates of PTSD in the 1739 sailors deployed to the Middle East between 2001-2005 1.6% The Guardian – 6th Feb 2013 – In 2012 across all branches of the US military and reserves there were 349 recorded In the same period 295 service members died In the same period 6500 ex-military personnel kil ed themselves. One every 80 minutes. Veteran Mental Health Ward 17 incorporates several services for the management of psychiatric illness in The Inpatient Unit Consultation Liaison Service which provides around 800 consultations a year to patients within RGH wards and to those who attend ARU. The Veterans Mental Health Rehabilitation Unit and Outpatients The PTSD Unit. Ward 17 is a 24 bed inpatient unit which manages acute and chronic psychiatric illness Currently approximately 70% of inpatients are entitled veterans and The other 30% include veterans without entitlements, families of veterans (especially war widows) and community patients Veterans have priority for admission Main diagnostic groups treated at Ward
PTSD Major Depression Anxiety Disorders Substance Use Disorders Ageing related disorders including early cognitive decline associated with psychological/psychiatric Less commonly we manage Schizophrenia and Bipolar Disorder Medical il ness Age related frailty Substance use Pain disorders Social issues of relationship strain, financial stress, homelessness, social isolation By themselves these are not usual The diagnosis of PTSD is made in the subset of people who have experienced trauma who are unable to cope with the consequences of trauma and whose well- being over time is greatly impacted by these consequences. ■Military combat ■Violent personal assault ■Natural and man-made disasters ■Severe motor vehicle accidents ■Rape ■Incest ■Childhood sexual abuse ■Diagnosis of a life-threatening illness ■Severe physical injury ■Hospitalization in an intensive care unit (ICU) Posttraumatic stress disorder (PTSD) has been described as "the complex somatic, cognitive, affective and behavioural effects of psychological trauma". PTSD is characterized by intrusive thoughts, nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance, and sleep disturbance, all of which lead to considerable social, occupational, and interpersonal dysfunction. 1. The person has been exposed to a traumatic event in which both of the
following were present-:
The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others The person's response involved intense fear, helplessness, or horror 2. The traumatic event is persistently re-experienced in one (or more) of the
fol owing ways-:
Recurrent and intrusive distressing recol ections of the event, including images, thoughts, and perceptions Recurrent distressing dreams of the event Acting or feeling as if the traumatic event were recurring Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event 3. Avoidance of stimuli associated with the trauma and numbing of
general responsiveness (not present before the trauma), as
indicated by three (or more) of the following-:
Efforts to avoid thoughts, feelings, or conversations associated with Efforts to avoid activities, places, or people that arouse recol ections of the trauma Inability to recal an important aspect of the trauma Markedly diminished interest or participation in significant activities Feeling of detachment or estrangement from others Restricted range of affect (e.g., unable to have loving feelings) Sense of foreshortened future (e.g., does not expect to have a career, marriage, children or a normal life span) 4. Persistent symptoms of increased arousal (not present
before the trauma) as indicated by two (or more) of the
Difficulty fal ing or staying asleep
Irritability or outbursts of anger
Exaggerated startle response
5. Duration of the disturbance (symptoms in criteria 2, 3 and
4) is more than 1 month.
6. The disturbance causes clinical y significant distress or
impairment in social, occupational, or other important
areas of functioning
DSM 5 – May 2013 Criteria A2 removed (person does not need to experience fear or horror at the time). An extra symptom cluster wil be added –the avoidance criteria wil be divided into active avoidance and numbing. PTSD wil be moved out of anxiety disorders into a new section "Trauma and stressor related disorders." Extra symptoms wil be added eg distorted blaming of others or self, persistent negative state, reckless or self destructive behaviour. The lifetime prevalence of PTSD ranges from 6.8 to 12.3 percent in the general adult population in the United States with one-year prevalence rates of 3.5 to 6 percent. In a study of 368 patients from a community primary care clinic, 65 percent reported a history of exposure to severe, potential y traumatic events; 12 percent went on to develop PTSD. Personal and societal factors appear to affect both the likelihood of developing PTSD after a traumatic event and the clinical presentation of PTSD. Risk factors for PTSD include lower socioeconomic status, parental neglect, family or personal history of a psychiatric condition, poor social support, and initial severity of reaction to the traumatic event The frequency with which PTSD occurs after a traumatic event is influenced by characteristics of the individual and the inciting event . Overall, women are four times more likely to develop PTSD than men, after adjusting for exposure to traumatic events The rates of PTSD are similar among men and women after events such as accidents (6.3 versus 8.8 percent), natural disasters (3.7 versus 5.4 percent), or sudden death of a loved one (12.6 versus 16.2 percent). Although women are more than 10 times as likely as men to be raped, the incidence of PTSD after rape is higher in men (65 versus 46 The rate of PTSD is lower in men than in women after events such as molestation (12.2 versus 26.5 percent) and physical assault (1.8 versus 21.3 percent). War-related PTSD has been associated with long- term consequences for mental health. A longitudinal cohort study compared a random sample of 450 Australian Vietnam veterans with matched subjects from the Australian general population. When assessed 36 years after the war, veterans with war-related PTSD were more likely than members of the general population to have depression, an anxiety disorder (eg, social phobia, panic disorder, agoraphobia with or without panic disorder, and specific blood phobia), alcohol dependence, or persistent pain disorder Most individuals who develop PTSD experience its onset within a few months of the traumatic event. However, epidemiologic studies have found that approximately 25 percent experience a delayed onset after six months or more . PTSD is commonly a chronic condition with only one-third of patients recovering at one year fol ow-up, and one-third still symptomatic ten years after the exposure to the trauma Individuals with one or more PTSD symptoms are more likely to experience occupational problems, have poorer social supports, and have more disability than controls. PTSD may increase the risk for attempted suicide. Individuals with PTSD have higher rates of problems in intimate relationships, including marital difficulties, compared to people without PTSD. Clinical Administered PTSD Description
The CAPS is the gold standard in PTSD assessment. The CAPS is a 30-item structured interview that corresponds to the DSM-IV criteria for PTSD. The CAPS can be used to make a current (past month) or lifetime diagnosis of PTSD or to assesses symptoms over the past week. Blake, Weathers, Nagy, Kaloupek, Charney, & Keane, 1995 Recent epidemiological studies indicate 12-month prevalence rates of 1.33% in Creamer M, Burgess PP, McFarlane AC. Post-traumatic stress disorder: findings from the Australian National Survey of Mental Health and Well-Being. Psychol Med 2001;31:1237-47 Most individual who develop PTSD do so without having suffered an ASD. (however ASD is associated with developing later PTSD) Hyperarousal symptoms at the time of the trauma are most predictive of a later diagnosis of PTSD. Severe combat associated stress is a predictor of PTSD. 30 years post Vietnam – 10% of veterans exposed to this form of stress continue to suffer Late onset PTSD can occur in 15-20% of sufferers – can occur many years later. There has been considerable interest in finding effective psychopharmacological strategies for treating posttraumatic stress disorder (PTSD). It is assumed that biological treatment may have an important role, given the abnormalities in neurotransmitter, neuroendocrine, and neuroanatomical systems that have been identified in patients with PTSD. So far, the mental health field has tended to focus on either biological or psychological targets. Maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Neurobiological Aspects of Autonomic Changes. Neuroimaging Neuroendocrine Epigenetics linked to neural changes. Increased neurological Alterations in fear conditioning, extinction learning, extinction retention and sensitization are likely to be involved in the development and/or maintenance of PTSD One of the earliest and most replicated PTSD findings is that of heightened autonomic reactivity (such as heart rate and skin conductance) and facial EMG reactivity to external, trauma-related stimuli, such as combat sounds and film clips, as wel as to internal, mental imagery of the traumatic event. Reactivity to trauma-related cues correlates with the severity of the disorder . Peri, T., Ben-Shakhar, G., Orr, S. P. & Shalev, A. Y. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47, 512–519 (2000).
Genetic influences account for 30%to 72% of vulnerability to PTSD. These estimates take into account genetic factors that may contribute to exposure to traumatic events, such as combat or interpersonal violence. Genetic influences on exposure to trauma are thought to largely function through heritable personality traits. Genetic risk factors that are common to major depression, generalized anxiety disorder and panic disorder also account for most of the genetic variation in PTSD identified to date. Thus, genes that affect the risk of developing PTSD also influence the risk of developing other psychiatric disorders, and vice versa. As with other mental disorders, influences on PTSD are probably polygenic; at least 17 gene variants have been associated with PTSD in at least one published study Neuro imaging abnormailities Pioneering sMRI studies found significantly smal er hippocampi in subjects with PTSD compared to trauma-exposed and non-trauma-exposed subjects without PTSD. Since then, a large literature has emerged, most of which, along with meta- analyses, has provided empirical support for a lower hippocampal volume in PTSD. Does it exist pre-morbidly, is it associated with trauma regardless of PTSD development?? Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P. & Bremner, J. D. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J. Affect. Disord. 88, 79–86 (2005)
Neuroendocrine abnormalities Catecholamines. Numerous studies have provided
compelling evidence for the presence of sympathetic nervous system hyper-reactivity in PTSD. It has been suggested that an excessively strong adrenergic response to the traumatic event may mediate the formation of the durable traumatic memories that in part characterize the disorder Indoleamines. The 5-HT system also appears to be
implicated in both the acute mediation of PTSD symptoms and the modulation of PTSD risk, as neuropharmacological, treatment and genetic epidemiological studies have indicated. Neuropeptide Y
Epigenetics and neural Increasing research into epigenetics Animal models mainly used. Focused on DNA hypermethylation of BDNF gene in hippocampal regions. Models in traumatised mice support the hypothesis that epigenetic marking of the BDNF gene may underlie hippocampal dysfunction produced by exposure to traumatic events. A recent study has identified another gene prone to changes in hippocampal region methylation – The transition of memories to a stable form is important for the persistence of PTSD and it is thus critical to understand the molecular mechanisms that underlie such memory stability in order to identify potential targets for pharmacological What changes in the amygdala are occurring to alter the way long term memories are stored? Epigenetic changes via methylation of several genes (including BDNF) implicated. Also changes in synaptic plasticity altered by epigenetic A limitation of the currently available studies is the lack of direct evidence for the mechanism through which DNA methylation and histone modifications at the cellular level get translated into altered circuit and behavioral function. However, the reviewed studies give us mechanistic insights, such as evidence that DNA methylation controls fear memory stability and that changes in DNA methylation in the adult CNS regulate the expression of known fear conditioning-related genes. Neuropsychopharmacology REVIEWS (2013) 38, 77–93 & 2013 American Col ege of Neuropsychopharmacology PTSD as a Biological and psychological Entity? A number of biological abnormalities have been found statistically to discriminate PTSD from non-PTSD control groups in various studies; on this basis, they may loosely be regarded as biomarkers. However, none of them possesses the specificity and sensitivity that is necessary to be used as a stand-alone diagnostic test for PTSD. The current ‘gold standard' for a PTSD diagnosis are the diagnostic criteria set forth in the fourth edition DSM IV. Biological Management of Pharmacoprohylaxis Manage sleep disturbance. Treat comorbidities. Psychopharmacology including management of intrusions, anxiety and re- Pharmacoprophylaxis Does it mean administering medications to the many who will never develop a Target the memory consolidation process which appears to occur in the presence of high levels of noradrenaline following a propanolol, morphine, gabapentine and hydrocortisone – limited evidence. An estimated 79% of women and 88% of men diagnosed with PTSD have at least one other psychiatric disorder; and 49% of women and 59% of men have three or more concurrent psychiatric diagnoses. Schoenfeld FB, Marmar CR, Neylan TC. Current concepts in pharmacotherapy for posttraumatic stress disorder. Psychiatr Serv 2004;55:519-31 Substance abuse Comorbidity of substance abuse is very high in PTSD patients. PTSD patients are at increased risk of abusing prescription Osser DN, Renner JA, Bayog R. Algorithms for the pharmacotherapy of anxiety disorders in patients with chemical abuse and dependence. Psychiatr Ann 1999;29:285–301. Psychotic symptoms in PTSD patients could indicate a comorbid psychotic disorder or could be part of the PTSD. Kozaric-Kovacic D, Pivac N. Quetiapine treatment in an open trial in combat-related post-traumatic stress disorder with psychotic features. Int J Neuropsychopharmacol 2007;10:253–61. Major depressive disorder History of major depression increases risk of developing PTSD, & PTSD diagnosis increases risk of Dysregulation of HPA axis may cause above associations. Responsiveness to antidepressants is diminished in PTSD patients with comorbid depression Breslau N, Davis GC, Peterson EL, Schultz LR. A second look at comorbidity in victims of trauma: the posttraumatic stress disorder-major depression connection. Biol Psychiatry 2000;48:902–9. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA,and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Stress 2008;21:530–9. Bipolar Disorder Dissociation (more serious pathology & less predictable response to pharmacotherapy) Sleep disturbance. Mounting evidence has implicated sleep impairment as a core symptom in PTSD and a primary source of distress and dysfunction for patients with this disorder. For many patients, sleep deprivation may exacerbate core daytime PTSD symptoms (hypervigilance, avoidance, reexperiencing), and these symptoms may improve when sleep Another justification for treating sleep difficulties first is the availability of prazosin, a psychopharmacology option that targets impaired sleep in PTSD patients and that has demonstrated substantial y larger effect sizes than medications commonly thought to be effective for the general symptom Spoormaker VI, Montgomery P. Disturbed sleep in posttraumatic stress disorder: secondary symptom or core feature? Sleep Med Rev 2008;12:169–84 Belleville G, Guay S, Marchand A. Impact of sleep disturbances on PTSD symptoms and perceived health. J NervMent Dis 2009;197:126–32. Sleep disturbances common in PTSD include the fol owing: 1. hyperarousal linked to difficulties initiating or 2. maintaining sleep 3. trauma-related nightmares 4. Awakenings without nightmare recol ection 5. prolonged sleep latency. Increased noradrenergic activity during sleep and while trying to fall asleep is thought to be an important Other causes of insomnia may contribute to the sleep difficulties of patients with PTSD. These include sleep apnea, restless leg syndrome, periodic limb movements of sleep, sleep hygiene issues, nicotine withdrawal, and medical problems associated with sleep fragmentation (e.g., pain and nocturia). Caffeine, though frequently employed as a method of coping with daytime symptoms of sleep deprivation secondary to PTSD and other causes of insomnia, can at times become a major independent contributor. Management of sleep Sedating antidepressants Benzodiazepines – potential for abuse Pharmacotherapy of PTSD The criteria for PTSD in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) include the symptom clusters of reexperiencing, These symptom clusters may differ in their responses to psychopharmacological treatment. It is less clear whether these differences depend on the nature of the trauma—for example, combat veterans versus survivors of rape or domestic abuse. Recently traumatized individuals may respond better than those with distant trauma, such as Vietnam veterans. SSRIs – FDA approval for paroxetine and sertraline. Mixed results in studies. Side effects often intolerable Sertraline has weaker evidence than paroxetine but has less side effects (sexual dysfunction, constipation, sedation, drug interactions, withdrawal and pregnancy risks) Citalopram could be considered but has less literature evidence. 4-12 weeks for adequate trial Other Antidepressants Some evidence for Venlafaxine, bupropion, mirtazepine and TCAs assisted with sleep and PTSD symptoms in some small studies. Intrusive flashbacks, olfactory and auditory experiences and paranoid thinking can respond to antipsychotic medication – both alone and as an augmenter of antidepressants. General hypervigilance and irritability/rage can also respond. Needs to be balanced against metabolic risks and other side effects. Evidence for quetiapine, risperidone and Prazosin is a generic alpha-1 adrenergic antagonist previously used to treat hypertension and symptoms of benign prostatic hyperplasia Well tolerated. Several small RCTs showing good effect size – especially for sleep improvement. Mood Stabilisers Valproate – no evidence Lamotrigine – no evidence Topiramate –some limited evidence for re- experiencing and numbing phenomena, alcohol cravings, pain and weight loss. (PBS approval for epilepsy and migraine) A Double-Blind Randomized Controlled Trial To Study the Efficacy of Topiramate in a Civilian Sample of PTSD, Mary S. L. Yeh, et al CNS Neuroscience & Therapeutics 17 (2011) 305–310 Beta blockers. – limited studies Clonidine – assists hyperarousal and sleep MAOIS – evidence for improvement. Aripiprazole – early evidence for assistance with decreased CAPs scores. The Psychopharmacology Algorithm Project at the Harvard South Shore
Program: An Update on Posttraumatic Stress Disorder
Laura A. Bajor, DO, Ana Nectara Ticlea, MD, and David N. Osser, MD. Harv Rev Psychiatry September/October 2011,Vol 19, number 5.
A Double-Blind Randomized Controlled Trial To Study the Efficacy
of Topiramate in a Civilian Sample of PTSD
Mary S. L. Yeh,1 Jair Jesus Mari,1,2 Mariana Caddrobi Pupo Costa,1
Sergio Baxter Andreoli,1 Rodrigo Affonseca Bressan1 & Marcelo Feijo´
Mello1CNS Neuroscience & Therapeutics 17 (2011) 305–310
Australian Centre for Post Traumatic Helath. Literature Reviews 2002-
Biological Studies of PTSD. Pitman,R. Rasmusson, A et Al.
Neuroscience, Vol 13, Nov 2012
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