Post Traumatic Stress Disorder (PTSD) – A Primer on Neurobiology and Management

DIAGNOSTIC CRITERIA FOR PTSD

The Diagnostic and Statistical Manual of Mental Disorders 5^th Edition (DSM-5) recognises several criteria for a PTSD diagnosis. The PTSD criteria are as follows:

1. Exposure to stressor – The individual was either directly or indirectly (witnessing, learning, or exposure to aversive details) exposed to trauma.
2. Intrusion symptoms (one or more required) – The trauma is persistently re-experienced via recurrent memories, nightmares, flashbacks, psychological distress, or physiological reactivity to traumatic reminders.
3. Persistent avoidance (one or more required) – Avoidance of trauma-related stressors: recurrent trauma-related thoughts or environmental reminders such as people, activities, and places that act as visual reminders.
4. Negative alterations in cognition and mood (two or more required) – Inability to recall key features, persistent (and often distorted) negative beliefs and expectations about oneself or the world, persistent distorted blame of self or others, persistent negative trauma-related emotions, markedly diminished interest in pre-traumatic activities, feeling alienated from others and constricted affect (persistent inability to experience positive emotions).
5. Alterations in arousal and reactivity (two or more required)– Disturbances to arousal and reactivity that began, or worsened, after the trauma are characterised by aggression, self-destructive or reckless behaviour, hyper-vigilance, exaggerated startle response, and difficulty concentrating or sleeping.
6. Duration – More than one month.
7. Functional significance – Trauma-related symptoms must cause psychological, social, or functional impairment.

Exclusion – Trauma-related symptoms cannot be attributed to anything else such as medications or substance abuse.

However, trauma outcomes vary across individuals, and this appears to be dependent on genetic susceptibility factors, history of prior psychological trauma, or an additional physical injury at the time of the traumatic event such as traumatic brain injury (TBI).

NEUROBIOLOGY OF PTSD

The neurobiology of PTSD is complex and involves neuroendocrine, neurochemical and neuroanatomical changes in neural networks.

Neuroendocrine Features:

The hypothalamic-pituitary-adrenal (HPA) axis is the central coordinator of how humans respond to stress. The stress response starts in the hypothalamus, where paraventricular neurons (PVN) secrete corticotropin-releasing hormone (CRH).

This hormone stimulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which stimulates the release of glucocorticoids (e.g. cortisol) from the adrenal cortex.

Cortisol exerts a negative feedback control of the HPA. Cortisol also reduces the noradrenergic stress response.

Sustained cortisol exposure has an adverse effect on the brain, particularly hippocampal neurons, resulting in impaired neurogenesis and neuroplasticity.

The hippocampus and prefrontal cortex have an inhibitory effect on HPA, while the amygdala and aminergic brain stem neurons stimulate the HPA.

Cortisol [Yehuda et al., 2015], [Sherin and Nemeroff, 2011]

• In PTSD, there exists a dysregulation of glucocorticoid signalling underpinned by heightened negative feedback sensitivity of the HPA. This results in low cortisol levels and blunted ACTH responses to CRH due to elevated levels of CRH, resulting in down-regulation of CRH receptors on the anterior pituitary.
• Two genes that are thought to be involved are NR3C1 (encoding the glucocorticoid (GC) receptor) and FKBP5 (role in immunoregulation and regulating the amount of GC available to the GC receptor)
• Evidence suggests that low cortisol at the time of exposure to trauma may predict the development of PTSD and that hypocortisolaemia may be a risk factor for the development of PTSD. This may explain why high dose hydrocortisone IV after trauma may prevent the development of PTSD. [Zohar et al, 2011]

Neurochemical Features: [Yehuda et al., 2015], [Sherin and Nemeroff, 2011]

Serotonin 

• Decreased serotonin transmission in the dorsal and median raphe is related to hyper-vigilance, increased aggression, impulsivity as well as the enhanced formation and resilience of intrusive memories providing a role for SSRIs in the treatment of PTSD.
• 3,4-Methylenedioxymethamphetamine (MDMA) is being studied in the treatment of PTSD as it increases serotonin levels. [Sessa, 2017]

Noradrenaline

• Noradrenaline (NA) mediates the stress response through central and peripheral mechanisms.
• In PTSD, there is increased noradrenaline transmission in networks that connect the locus coeruleus to the amygdala and hypothalamus (the noradrenergic feed-forward circuit).
• The enhanced NA release is associated with increased fear conditioning and enhanced encoding of emotional memories with increased arousal and vigilance.
• For example, yohimbine, an α2-adrenergic receptor antagonist, increases NA release, inducing flashbacks and increased autonomic responses in patients with PTSD.
• Along the same lines, propranolol administration (β2-adrenergic antagonist) after exposure to trauma can reduce PTSD symptom severity and reactivity to trauma cues. 

Dopamine

• Dopamine is implicated in the regulation of fear conditioning and anxiety. In addition, in individuals with PTSD, there is a genetic component associated with dopamine metabolism that governs whether an individual develops PTSD and what symptoms they may display.
• Hypodopaminergia (due to genetic or epigenetic effects) is associated with an increased risk of developing PTSD. Combat stress responses have shown significant elevations of dopamine release (100 times above the resting state). This dopamine depletion combined with trait hypodopaminergia is postulated in the pathogenesis of PTSD. Hypodomainergia related to reward may also be linked to an increased risk of substance use disorders. [Blum, et al,2019]

Others

• Glutamate (excitatory) release via the NMDA receptors involved in synaptic plasticity, learning and memory.
• GABA (inhibitory) release mediating anti-anxiety effects.
• Proinflammatory cytokines involved in neuroinflammation
• Endocannabinoids (anandamide, 2-arachidonoylglycerol) mediate memory consolidation via CB1 receptors.
• Neurosteroids (allopregnanolone) have an inhibitory effect on glucocorticoid and NA signalling.
• Neuropeptides (neuropeptide Y, enkephalin endorphins, BDNF and DHEA)

Neuro-anatomic Features

Using structural brain imaging, circuits that are associated with adaptation to stress and fear conditioning have been shown to be structurally altered in patients with PTSD.

Hippocampus

• Reduced hippocampal volume is a hallmark feature of PTSD. The hippocampus plays an important role in fear extinction and conditioning, stress responses and declarative memory.
• Stress via enhanced cortisol secretion is known to impair hippocampal neurogenesis and damage hippocampal neurons, which may explain the smaller hippocampal sizes found in patients with PTSD. [Blum et al., 2019]
• However, a recent study postulates that smaller hippocampal (left) volume is a risk factor in the persistence of PTSD as opposed to a result of PTSD. [Bremner et al., 2011]

Amygdala

• The amygdala plays a crucial role in emotional processing and the acquisition of fear responses.
• The amygdala remembers a stressful response by increasing glutamate transmission, consolidating the traumatic memory via NMDA receptor activity. Upon future exposure to a traumatic reminder, a fear response is activated.
• Structural MRI analysis has revealed pathological damage to the amygdala, which was associated with a hyper-responsive reaction to subliminally threatening cues. [Van Rooij et al., 2015]
• Individuals with PTSD may show hypo- and hyper-activity within distinct regions of the amygdala sub-nuclei.
• Downstream from the amygdala is the Periaqueductal gray (PAG), an important site mediating fear responses such as flight/ fight or freeze responses.

Medial prefrontal cortex (PFC)

• The medial PFC (contains the anterior cingulate cortex (ACC)) is connected to the amygdala and has inhibitory control over its stress responses and emotional reactivity to different stimuli.
• The medial prefrontal cortex mediates fear extinction through inhibition of acquired fear responses.
• Decreased frontal cortex and ACC volumes are found in patients with PTSD.
• In PTSD, a decreased PFC volume correlates with symptom severity due to decreased inhibitory control over the amygdalar stress response.

PTSD PHENOTYPES

The dynamic interaction between the medial prefrontal cortex and the amygdala creates two distinct phenotypes in PTSD patients. [Yehuda et al., 2015]

INTEGRATED MODEL OF PTSD

Three key brain networks have been identified as central to higher cognitive function:

• Salience network (detection of salient internal and external stimuli)
• Default mode network (emotional regulation, social cognition, future thinking and autobiographical memory)
• Central executive network (cognitive function)

The anterior insula acts as a switch between engaging the executive network and disengaging the default mode network allowing for better functioning of higher cognitive processes.

Abnormalities in these three areas are associated with specific clinical symptoms in PTSD as shown in the diagram below. [Yehuda et al., 2015]

TREATMENT OF PTSD

PTSD develops through a combination of psychological and biological mechanisms.

Treatment modalities aim to address the various psychological and biological components.

In some cases, a combination of medication and psychotherapy is required.

Two important concepts in PTSD treatment are:

1. Kindling – Process through which increasingly low severity stimuli can activate negative responses over time
2. Sensitisation – When people are repeatedly exposed to negative stimuli, progressively greater responses develop over time.

Treatment aims to achieve fear extinction, desensitisation and intervene in the kindling process.

Psychotherapy

Psychotherapy is considered a first-line therapy and can be divided into trauma-focused and non-trauma-focused psychotherapy.

Important: Psychological debriefing is not recommended. Providing information, emotional support, and practical assistance is recommended for individual psychological debriefing.

Trauma-focused CBT has been most extensively studied and shown to be effective.

Prolonged exposure therapy and cognitive processing therapy are two types of trauma-focused CBT. They are based on the principles of extinction learning, habituation and desensitisation.

Trauma-focused therapy 

• Prolonged exposure therapy (PET): Progressive exposure to the trauma narrative and trigger settings.

• Cognitive-processing therapy (CPT): Involves writing a trauma narrative and repeatedly reading it as a means to expose the trauma memory. It also addresses shame, guilt or feelings of mistrust. In this sense, culturally-adapted CBT has also been useful as this technique offers a more specific paradigm to treat PTSD.

• Narrative exposure therapy (NET): A short-term approach involving the chronological cataloguing of their lives and an in-depth detailing of all traumatic events. This therapy was developed for the survivors of the Pinochet regime in Chile and has proven to be very useful in overcoming trauma. It is recommended for adults with PTSD where trauma is linked to genocide, civil conflict, torture, political detention, or displacement.

• Eye Movement Desensitization and Reprocessing (EMDR)

EMDR is a “A therapy aiming to process distressing memories by having the patient recall distressing images while receiving one of several types of bilateral sensory input, including side-side eye movements” – Yehuda et al., 2015

• Stress inoculation training (SIT): Can be considered for adults with PTSD where trauma-focused cognitive behavioural therapies or EMDR are unavailable or unacceptable.

Non-trauma-focused therapy

• Supportive therapy
• Non-directive counselling
• Mindfulness and patient-centred therapy
• Interpersonal therapy
• Yoga and mindfulness training

“Patients with a history of interpersonal violence, early life trauma or those with a complex presentation of PTSD that includes emotional detachment might be better treated with phase-oriented approaches.

Phase oriented approaches involve skills training, mood regulation and grounding, identifying attachment schemas and developing competence in social interactions.

Once these skills have been developed, the patient can then participate in modified exposure-based therapy focusing on emotional stability and negative personal schemas.” – Yehuda et al., 2015

This type of PTSD is often called complex trauma disorder or complex PTSD. Prof. Kulkarni talks about trauma and complex trauma disorder in women. A/Prof. Sathya Rao discusses the overlap of complex trauma disorder with Borderline Personality Disorder.

 Pharmacotherapy [Yehuda et al., 2015] 

“Current evidence favours selective serotonin reuptake inhibitors as the class with the most evidence supporting their use as first-line psychopharmacological treatment options.” – Yehuda et al., 2015

A recent systematic review, commissioned by the WHO, showed that although some SSRIs are statistically superior to placebo, the effect size is small. [Koenigs and Grafman, 2009]

When reviewing methodologically robust pharmacotherapy trials, Hoskins and colleagues found that amongst antidepressants, only fluoxetine, sertraline, paroxetine, and venlafaxine have statistically significant data on reducing PTSD symptoms compared to placebo. Quetiapine has evidence when used as monotherapy. Prazosin and risperidone show benefits as augmentation agents. [Hoskins et al, 2021]. 

Many other interventions are currently used off-label to treat PTSD, and these drugs are based on the neurobiology of PTSD symptoms. These include:

• Antidepressants – In addition to paroxetine and sertraline, phenelzine, imipramine, desipramine, amitriptyline, fluoxetine, brofaromine, bupropion, and mirtazapine are the favoured first-line treatment option.

• Antipsychotics – Dopaminergic blockade with risperidone, olanzapine, and quetiapine; however, cardiovascular and metabolic side-effects mean that extra caution is advised when prescribing these agents.

• Anticonvulsants – Valproate, carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, and tiagabine can be prescribed as monotherapy or as an adjunctive treatment for their GABA potentiating and anti-kindling effect.

• Anti-adrenergic drugs (α1, α2 and β receptors) – Examples include prazosin, guanfacine, alfuzosin, doxazosin, propranolol and clonidine, which have been used as a treatment strategy for PTSD-related nightmares.

• Other experimental treatments – D-cycloserine (glycine receptor agonist), endocannabinoids, neuropeptides (NPY antagonists, cholecystokinin antagonists, substance P antagonist, and nalmefene (endogenous opioid antagonist)), ketamine, mifepristone and hydrocortisone.
• Neuromodulation: There is no evidence that rTMS or ECT reduce PTSD symptoms however they may be effective in patients with refractory depression and comorbid PTSD. There are case reports of Deep Brain stimulation (DBS) showing efficacy in PTSD and trials are underway. [Du, et al, 2022]

Important:

Benzodiazepines can exacerbate avoidance and depressive symptoms most likely due to their strong sedative, addictive, and dissociative properties. [Du, et al, 2022]

Prazosin in PTSD: 

• Prazosin shows good evidence in the treatment of PTSD with a positive effect on PTSD scores, nightmares and sleep quality. [Reist et al., 2021]. 
• Treatment of PTSD with prazosin is usually initiated at a dose of 1 mg, with monitoring for hypotension after the first dose. The dose is then gradually increased to maintenance levels of 2-6 mg at night. Studies of military patients with PTSD have used higher doses (e.g., 10-16 mg at night) with the maximum dose used clinically without side effects at 50 mg /day. [Koola et al, 2014]. 
• Due to its short half-life, BD or TDS dosing may be required.
• Clonidine, an alpha-2 presynaptic agonist, is also effective for nighttime symptoms of PTSD.
• View the video on prazosin and clonidine. 

Propranolol in PTSD: 

• In PTSD, reactivated memories become temporarily labile and require stabilisation which is known as reconsolidation.
• As PTSD is associated with a hyper-noradrenergic state and, β-noradrenergic receptor stimulation has been found to facilitate emotional memory reconsolidation, using a β-noradrenergic receptor antagonist may prevent traumatic memory reconsolidation and thus may help in addressing intrusion symptoms of PTSD. [Roullet et al, 2021]
• Propranolol administered prior to trauma memory reactivation decreased the severity of PTSD symptoms, reduced physiological responses (e.g., heart rate, skin conductance, blood pressure), and improved cognitive performance in individuals with PTSD. [Young & Butcher, 2020]
• When used as a preventative measure following trauma, propranolol did not significantly reduce the risk for subsequent PTSD.
• Trial is ongoing to explore the effect of post-reactivation propranolol. (up to 2-3 mg/kg dose)

Hydrocortisone: 

• 30 mg oral hydrocortisone or placebo prior to prolonged exposure (PE) was associated with greater reduction in total PTSD symptoms in a small study. [Yehuda et al, 2015]

According to a systematic review and meta-analysis: [Astill Wright et al, 2019]

The limited evidence for hydrocortisone and its adverse effects mean it cannot be recommended for routine use, but, it could be considered as a preventative intervention for people with severe physical illness or injury, shortly after a traumatic event, as long as there are no contraindications. 

• Initiating a therapy within the ‘golden’ first six hours post-trauma is thought to be crucial to impeding the disruption to memory consolidation that occurs within this period. However one study showed benefits outside this period ( within 12 hrs) as well. High dose IV (100-400 mg single dose) was used in one study in prevention.

Algorithm for Pharmacological Management of PTSD. 

• SSRIs are considered first-line pharmacological treatments. Fluoxetine, Sertraline and Paroxetine have the best evidence for efficacy. Amongst SNRIs, Venlafaxine has the best evidence.
• Augmentation of SSRI or quetiapine is recommended in the context of marked agitation.
• Trazodone 50mg-100mg night, quetiapine or prazosin are recommended as augmentation strategies if insomnia is present.
• Mirtazapine is recommended as 4th line treatment.

Clinical Pearls:

PTSD is co-morbid unless proven otherwise. Diagnostic overshadowing, whereby symptoms are attributed only to trauma, may result in misdiagnosis and inadequate treatment.

Therefore, it is crucial for clinicians to diagnose and treat any other comorbidities.

CONCLUSION

Traumatic stress has a broad range of effects on the function and structure of discrete regions of the brain that have critical roles in emotion, memory, and reactivity.

PTSD is best understood as a heterogenous disorder with different phenotypes based on the brain circuits involved. Co-morbidity is high and clinicians should always be vigilant for the presence of other psychiatric disorders.

QUIZ