الرحمن الله بسمالرحيم

GAZAPTSD vs FAITH

Role of PsychiatryMenan Abd El Maksoud Rabie, MD

Associate Prof. of Psychiatry, Faculty of medicine, Ain Shams University

Member, Egyptian Psychiatric Association (EPA)Associate member, International Federation of Psychiatric Epidemiology (IFPE)

Managing Editor, Journal of Middle East Current Psychiatry (MECPsych)Deputy Chair, Research Unit, General Secretariat of Mental Health, MOH, Egypt

Contents • Epidemiology (Prevalence, Risk factors)• Clinical presentation• History & Classification• Research • Neural circuits• Pharmacological approaches• Faith and its effect• Conclusion

Epidemiology

PrevalencePTSD results from exposure to a traumatic event which evoked

fear, helplessness and horror. Old studies estimated the prevalence of PTSD in the adult

population between 1-2% (Helzer, Robins, & McEvoy, 1987; Kulka,

Schlenger, Fairbank, Hough, Jordan, Marmar, & Weiss, 1988; Keane, 1989)

Recently, PTSD was affecting (10-15%) of people exposed to traumatic events, with a lifetime prevalence of 6.8% in the US.

(Kessler et al., 2005).

Currently, “broadly defined” PTSD affects 5.6% (3% by DSM-V, and 4.4% by ICD-10). In this recent study 67.1% reported one or more traumatic events, 75.4% of them reported more than one trauma.

(Stein et al, 2014).

Risk factors• PTSD occurs in both forms,– acute (immediately following incident) – chronic (seek treatment many months after event)

• Symptoms vary acc to types, intensities, frequencies (e.g. multiple rapes), duration of a traumatic event (e.g. an ongoing incestuous relationship), sex and age of the individual at the time of the event.

• 60% of patients had a troubled childhood and/or adolescence including involvement in street gangs, child abuse, or alcoholic parents.

Keane, 1989

PTSD in GAZA

• 2008-2009 ‘Cast Lead’ war • More than half of 15 to 18 year olds (358) in Gaza

show signs of PTSD after seeing dead bodies and witnessing heavy shelling.

• Of those, 29.8 % had symptoms of full PTSD, and 34.3 % had symptoms of partial PTSD.– 91 % of teenagers reported seeing mutilated bodies on

TV, – 88.5 % heard artillery shelling, – 86.6 % had seen the aftermath of shelling, and – 86 % had heard the sound of war planes overhead.

PTSD in GAZA

• The toll on the mental health of these young people tends to be exacerbated by crowding and poverty, which is endemic in Gaza

• Each cycle of violence has a cumulative effect on children and young people.

• After the 2012 war, the PTSD rate among children in Gaza doubled, according to the United Nation’s agency for Palestinian refugees (UNRWA).

PTSD in GAZA

• Gaza 2014• > 1,800 people have died and

33,000 have lost their homes over the past couple of months as a result of the fighting between Hamas and Israel

Research on PTSD

Earliest Articles• Flooding

for combat-related stress disorders: Assessment of anxiety reduction across traumatic memories, Fairbank,, Keane, 1982, Behavior Therapy, 42

• PTSD. An inpatient treatment unit., Adams, 1982, American Journal of Nursing, 1

• PTSD. The victims who survived., Norman, 1982, American Journal of Nursing, 0

• Interpersonal problems of Vietnam combat veterans with symptoms of PTSD, Roberts, 1982. Journal of Abnormal Psychology, 43

• A psychophysiological study of PTSD in Vietnam veterans, Blanchard et al, 1982, Psychiatric Quarterly, 74

• PTSD and the insanity defense: A critical analysis, Packer, 1983, Journal of Psychiatry and Law, 7

• The Vietnam Veterans on trial: The relation of PTSD to criminal behavior, Wilson, Zigelbaum, 1983, Behavioral Sciences and the Law, 11

• PTSD, Vietnam veterans and the law: A challenge to effective representation, Erlinder, 1983, Behavioral Sciences and the Law, 6

Era of Vietnam Veterans• PTSD appeared clinically through comorbidity

with SU, somatoform & affective disordersJelinek and Williams, 1984

Predators also have PTSD…• In one southern city of

Sderot alone, a recent study by NATAL, the Israel Trauma Center for Victims of Terror and War, estimates that between 75 % and 94 % of all the children aged 4 to 18 demonstrate symptoms of PTSD.

History & Classification

History & Classification

• Psychological effects of combat, “shell shock” or “combat fatigue” World War 1 transient anxiety reactions. Clinical interest declined after the war.

• World War II symptoms of startle reaction, nightmares, and irritability.

DSM-I traumatic neurosis. DSM-II Transient Situational Disturbances and

Adjustment Reactions.DSM-III (1980) PTSD.

Keane, 1989

History & Classification

• Appearance of PTSD in DSM-III was a reaffirmation of the unique characteristics and symptoms among individuals who survived life-threatening and disastrous experiences.

• Its first appearance ICD is of more recent date (WHO, 1992)

• DSM-IV (1994) PTSD was categorized as an anxiety disorder.

• DSM-V (2013) trauma-based disorders in a trauma or stress.

(Moreau and Zisook, 2002, Vermetten and lanius, 2012).

Clinical Presentation

Traumatic event universally…

Death of a childhood friend in combat, a sense of extreme violation of religious principles, the killing of small children, or injuries with loss of a limb.

A single recognizable stressor was present in (73%). The remaining patients may have had a discrete stressor (cryptotrauma) that was never elucidated during the interview process.

Birkhimer, DeVane, and Muniz, 1985

Traumatic events in Gaza• One young Palestinian boy reported witnessing his

brother’s decapitation when metal from an Israeli bombing tore off the victim’s head as he slept.

Traumatic event

• “The main thing we’re facing in Gaza is that many organizations haven’t finished their work yet with children affected in the last attacks, and here we go with a new offensive”.

All the things that can help adults – social networks, previous

experiences and so on – are not available for children

Clinical picture challenge

a symptom complex of Depression-related symptoms (sleep difficulties,

social withdrawal, suicidal ideations or gestures, decreased appetite, low self esteem, crying spells, decreased motivation, and sexual dysfunction),

Anxiety-related symptoms (palpitations, tremor, hyperalertness, and dizziness),

Poor social functioning (anger or hostility, poor employment history, marital problems, poor impulse control, physical violence, poor interpersonal relationships, and legal problems).

Birkhimer, DeVane, and Muniz, 1985

Clinically….

PTSD is characterized by 3 symptom clusters,(1)Hypermnesia for the core traumatic event,

(1)re-experiencing in form of flashbacks and nightmares, (2)aversive memories triggered by sensorimotor cues, (3)disturbed memory for peritraumatic events,

(2)Hyperarousal (1)exaggerated startle, (2)hypervigilance (3)irritability

(3)Avoidance of reminders associated with the trauma.

Clinically ….• Early symptoms detachment, aggression,

insomnia, bed-wetting and nightmares. • Children terrified to be left alone, • experiencing sleep disorders, • aggressive or uncommunicative, and • losing the ability to concentrate.

Now trauma is living in us again. Even closing the door of the fridge can scare my daughters,” Umm Fadi, Tal al-Sultan

Clinically ….

• Studies in Vietnam, Palestine, and Kuwait suggest that children who witness intense violence at a young age will suffer stress disorders that can affect their neurobiology, development, and cognition, thereby scarring them permanently.

• Children who suffer stress disorders also risk developing full-blown PTSD, which can give rise to suicidal thoughts and violent behavior later in life.

• “It’s hard to explain politics to children — they hear from other children that it’s Israel bombing Gaza again, but still I can’t give them an answer as to why,” she said, adding: “I am afraid myself, and my children come to hide in my bedroom. How can I possible show them I am not afraid.”

Neural Circuits in PTSD

Neural circuits and substrates implicated in PTSD

• PTSD is a maladaptation to a traumatic stressor, with altered fear-related learning and extinction, behavioural sensitisation /kindling, and alterations in brain areas and neurotransmitter systems closely linked to these processes.

• Literature focuses on the corticolimbic circuit, with neuroimaging studies reporting abnormalities in the prefrontal cortex, hippocampus and amygdala

(Milad and Rauch, 2007; Quirk and Mueller, 2008)

fear learning abnormalities and sensitization.

• Insufficient top-down control from the PFC to the amygdala impaired extinction of fear-related memories (Koenigs and Grafman, 2009; Milad et al., 2009) and executive control over fear responses (Aupperle et al., 2011).

• Poor hippocampal-PFC signalling may also underlie contextual memory deficits in PTSD poor control of conditioned fear responses (Acheson et al., 2011).

Glutamate & GABA

• The main projections from the PFC to the amygdala are glutamatergic in nature

(Del Arco and Mora, 2009).

• Insufficient top-down control from the PFC to the amygdala implies involvement of glutamatergic pathways in PTSD, either directly or indirectly.

• Fear extinction requires PFC-activation of intercalated cells in the amygdala by GABAergic interneurons that inhibit local activation

(Likhtik et al., 2008).

HPA activity• PFC inhibits HPA activity via a glutamatergic projection to

the bed nucleus of the stria terminalis (part of amygdala), which activates a GABAergic inhibitory projection to the CRF neurons in the hypothalamic paraventricular nucleus (PVN) (Radley et al., 2009).

• PTSD patients exhibit increased CSF levels of CRF (Baker et al., 1999; Bremner et al., 1997) and abnormalities in pituitary adenylate cyclase-activating polypeptide, PACAP, (Ressler et al., 2011)

• suggests utility of compounds that dampen the CRF system in the treatment of PTSD (Baker et al., 2009).

Pharmacological approaches

• They differ depending on whether treatment focuses on the development aspects of PTSD or whether it aims at treating chronic PTSD – Preventive intervention around the time of trauma

when processes that could lead to PTSD may be initiated

– Or symptom reductionSteckler & Risbrough, 2012

TARGETS FOR PREVENTION

Prevention• preventive pharmacological treatment

before the traumatic event may be feasible. (prospective or primary prevention)

• Preventive treatment given shortly after the traumatic event, but before symptoms develop. (retrospective or secondary prevention) aims at preventing or blocking the induction or consolidation of PTSD

GR antagonists, CRF1 antagonists and CCK2 antagonists

• Blockade of the GR prior to exposure to stressor prevented the development of fear responses

(Kohda et al., 2007),

• CRF1 receptor antagonism prevented the initiation of stress effects (Adamec et al., 2010), and similar findings have been reported with CCK2 antagonism (Adamec et

al., 1997). Via inhibition of the HPA axis or via central effects at limbic circuitry

• Beneficial prior to the occurrence of the trauma.

GR antagonists, CRF1 antagonists and CCK2 antagonists

• Drug effects in Primary Prevention may be carried over to post-stress conditions reflecting secondary prevention.

• It has been shown that the protein synthesis inhibitor anisomycin, administered either shortly before or after predator stress, also attenuated anxiety-related behaviour in rats

Cohen et al., 2006

Noradrenaline

• hyperreactivity of the noradrenergic system persist in PTSD and mediate hyperarousal symptoms and sleep disturbances

(Southwick et al., 1999a; Liberzon et al., 2005; Raskind et al., 2003).

• Increased NA signalling at the amygdala and hippocampus may facilitate retrieval of aversive memories

(Southwick et al., 1999b)

Adrenoceptor agonists and antagonists

• prevention of presynaptic NA release with a2 adrenoceptor agonists or opioids. Dexmedetomidine blocks fear consolidation

(Davies et al., 2004)

• Blocking post-synaptic noradrenaline receptors less efficacious. Prazosin failed to block stress-related behaviour (Adamec et al., 1999)

• BB, propranolol is the most promising candidate drug for intervention after a traumatic event (Pitman and Delahanty, 2005). Efficacy in preventing trauma-related physiological reactivity (Pitman et al., 2002)

Serotonin

• Polymorphism of the 5-HT transporter with traumatic events is a susceptibility factor for PTSD

(Lee et al., 2005; Grabe et al., 2009; Xie et al., 2009).

• Stress increase 5-HT neurotransmission in frontal cortex, hippocampus and amygdala (Linthorst, 2005).

• SSRIs are also efficacious in treating the disorder, suggestive that 5-HT play a role in the pathogenesis.

(Bandelow et al., 2008; Krystal and Neumeister, 2009)

Cortisol

• In PTSD, lower 24 h cortisol levels are reported d.t. enhanced negative feedback inhibition of the HPA axis by glucocorticoids and/or hyporeactivity of the adrenals or the hypothalamus (Yehuda, 2005).

• low cortisol levels re-experiencing of traumatic event, facilitate retrieval of aversive memories

(De Quervain et al., 2009)

• A greater reactivity of the HPA axis to stressors potentially facilitate reconsolidation of aversive memories (Taubenfeld et al., 2009)

NMDA-R and GABAergic compounds

• A group of burned service men treated with the NMDA receptor antagonist ketamine had lower incidence of PTSD.

(McGhee et al., 2008)

• Novel pharmacological tools targeting NMDA receptor subunits could be of benefit while avoiding some of the side effects inherent to NMDA receptor blockade. (Steckler & Risbrough, 2012)

Benzodiazepines

• BDZ facilitate memory for events that occurred just prior to treatment (Hinrichs et al., 1984), due to blockade of active interference during consolidation.

• Secondary prevention with BDZ has no effect (Gelpin et al.,1996; Mellman et al., 2002) or could even increase the likelihood of victims to develop PTSD.

• Lack of efficacy may be due to the difference in efficacy of BDZ to induce retrograde versus anterograde amnesia, BDZ disrupt active associative processes and only affect consolidation when very high doses are used (Cahill et al.,1986; Jensen et al.,1979)

Opioids

• Morphine administration shortly after the traumatic event reduces the likelihood to develop PTSD (Saxe et al., 2001; Bryant et al., 2009; Holbrook et al., 2010).

• Mechanism unknown, possibly via an indirect reduction in NA activity, or a direct action at intercalated cells in amygdala critical for fear extinction processes (Likhtik et al., 2008).

Treatment of Established

PTSD

SSRIs• SSRIs have shown efficacy in reducing symptom severity and

in relapse prevention (Van der Kolk et al., 1994; Connor et al., 1999; Brady et al., 2000; Martenyi et al., 2002; McRae et al., 2004; Davidson et al., 2006; Onder et al., 2006),

• Although only 60% of patients respond to treatment and only about 20-30% of patients achieve remission (Stein et al., 2002; Zohar et al., 2002)

• SSRIs still suffer shortcomings (delayed onset of action, partial response with residual symptoms, or non-response, and undesirable side effects (e.g., loss of sexual drive, gastrointestinal effects, changes in body weight) which limits their utility and indicates a major unmet medical need for novel treatment approaches in PTSD.

Other ADD

• Although ADD showed therapeutic utility in clinical trials, they have not become first line treatment for PTSD, because they are less well tolerated (Bandelow et al., 2008).

• Although the primary mechanism of action differs amongst ADD, all of them – interact with 5HT & NA systems. – normalize HPA axis activity in response to stress – enhance hippocampal neurogenesis , which may represent

a final common pathway. (Reul et al., 1994; Gold et al., 1995; Matheson et al., 1997; Stout et al., 2002; Xu et al.,

2006; Kasper and McEwen, 2008; Szymanska et al., 2009; McEwen et al., 2010)

Adrenergic agonists and antagonists

• Blockade of the a1 adrenoceptor with the a1 adrenoceptor antagonist prazosin has been reported to improve various PTSD symptoms, but in particular sleep and nightmares (Peskind et al., 2003; Raskind et al., 2003, 2007; Taylor et al., 2008).

• A recent comparison study of prazosin and quetiapine for ameliorating night-time sleep disturbance indicates better overall tolerability of prazosin (Byers et al., 2010)

Atypical APDs

• Atypical APD are largely used as adjunctive therapy, but only a limited number of randomized, double-blind, placebo controlled clinical trials have been reported with risperidone and olanzapine, leading to mixed results (e.g., Butterfield et al., 2001; Stein et al., 2002; Hamner et al., 2003; Monnelly et al., 2003; Reich et al., 2004; Padala et al., 2006).

Cannabinoid Receptor Agonists• Another interesting pharmacological approach the

manipulation of the cannabinoid system• Clearly, treating patients with CB1 agonists would be

problematic, because of the abuse risk. • indirect manipulation of the endocannabinoid

system, by inhibition of fatty acid amide hydrolase (FAAH), prevents degradation of endogenous endocannabinoids such anandamide.

• Interestingly, anandamide administration into the hippocampus blocked reconsolidation of fear conditioning (De Oliveira Alvares et al., 2008)

• attenuate reconsolidation processes in PTSD.

FAITH or FEAR

Fear extinction• PTSD pts are impaired in extinction of learned

fear with impairment predicting symptom severity (Norrholm et al., 2011).

• Extinction is a process whereby a learned fear response is reduced via repeated presentation of the conditioned stimulus, i.e., a trauma-related cue, in the absence of the unconditioned stimulus.

• It is considered to be a process whereby new memories are formed, i.e., the patient learns that the CS is not necessarily associated with the US.

FAITH• ALLAH.• The Judgment day.• The PARADISE FOR

MARTYRS.• Defending their right,

their land and their honor.• Will die for their target.• Family and “kind world”

Support.

Conclusion

The problem here in Gaza is that we are living in a high level of stress and ongoing trauma.

No one can guarantee that this will not happen again…

PTSD effect is magnified by the feelings of worthlessness, helplessness and hopelessness. GAZA has them all: “WORTH”, “HELP” and “HOPE”....