Anxiety Disorders    Bipolar Disorder    Dementia    Depression    Epilepsy    Migraine    Multiple Sclerosis    OCD    Panic Disorder  
  Parkinson's Disease    PTSD    Schizophrenia    Sleep Disorders    Stroke  
 

More maps of the brain
    Forebrain
    Midbrain
    Hindbrain
    Spinal cord
    Lobes
    Limbic system
    Coronal section
    Cerebral vasculature

 

Post-traumatic Stress Disorder (PTSD)

Aetiology

Despite the fact that an environmental event is by definition the trigger for PTSD, there are several reasons to believe that pharmacotherapy plays an important role in the treatment of this disorder. There is increasing evidence that PTSD is not simply a normal response to stress, but rather that it represents an abnormal or disordered reaction (Yehuda and McFarlane, 1995). This abnormal reaction appears to be mediated by specific neurochemical and neuroanatomical dysfunctions (van der Kolk, 1997).

Neurobiology

Many parts of the brain are likely to be involved in PTSD.  However, in recent studies two structures in particular have been highlighted - the amygdala   and the hippocampus  . The amygdala receives inputs from the thalamus   and the cortex, and sends efferents to the brainstem  , hypothalamus   and striatum. It is possible that these circuits are important in responding to threatening information from the environment via the autonomic, neuroendocrine and motor systems. Preclinical studies indicate that amygdala circuits are involved in fear conditioning and extinction (Charney et al., 1993). For example, if a rat is shocked each time it hears a particular noise, it develops a fear of that noise (conditioning). The thalamo-amygdala pathway may allow a rapid fear response to perception of the noise.  If the rat is then repeatedly exposed to the same noise without being shocked it gradually loses the fear (extinction).  This may involve the slower cortical-amygdala pathways, which perhaps inhibit the earlier associations.

The hippocampus receives inputs from and sends efferents to both amygdala and the cortex.  The hippocampus plays an important role in memory, and these circuits may be involved in mediating explicit memories of traumatic events and in mediating learned responses to a constellation of cues ("contextual fear conditioning").  Furthermore, preclinical studies demonstrate death of hippocampal neurons and hippocampal shrinkage after exposure of animals to chronic stress.  This reaction may be mediated in part by hippocampal glucocorticoid receptors (Charney et al., 1993).

Most recently there has been clinical confirmation of amygdala and hippocampal involvement in PTSD (Rauch et al., 1998).  Positron emission tomography (PET) studies show that veterans with PTSD demonstrate increased right amygdala activity when exposed to combat movies.  Magnetic resonance imaging (MRI) studies show that both male combat veterans and women survivors of childhood sexual abuse with PTSD have lower hippocampal volumes.  In some of these studies, decreased volume of the hippocampus correlated with trauma exposure or memory deficits.

PTSD is characterised by traumatic memories that seem different from other kinds of memories.  Such memories continue for many decades, they are easily triggered, and their affect-laden quality can make them difficult to translate into words.  Memory in PTSD patients is also characterised by different kinds of impairment, including not being able to remember aspects of the trauma and fragmentation of memories.  These clinical symptoms are entirely consistent with current evidence of dysfunction in the amygdala and hippocampus - which are important structures in the "emotional memory system" of the brain.

From a neurochemical perspective, several neurotransmitters systems are likely to be involved in PTSD.  These include the noradrenaline, dopamine, opioid and serotonin systems.  In addition, it is likely that the hypothalamic-pituitary-adrenal (HPA) axis is important in this disorder.   An emerging theme in the literature is that sensitisation of neurochemical systems is a crucial pathophysiological characteristic of PTSD (Charney et al., 1993;  Yehuda, 1998).

Some studies have found increased release of noradrenaline and increased autonomic activity in PTSD.  Furthermore, patients show increased responsiveness to the a2 autoreceptor antagonist, yohimbine.  In response to excessive adrenergic function there may be post-synaptic down-regulation of adrenergic receptors.  Thus, despite a relatively normal baseline firing rate, small perturbations may result in increased release of noradrenaline (sensitisation).

The dopamine system may also demonstrate sensitisation.  In preclinical paradigms it can be shown that different  pharmacological and environmental stimuli are cross-sensitisers of dopaminergic forebrain pathways. For example, initial environmental stress may result in a greater than usual response to dopamine agonists like cocaine.  Patients with PTSD sometimes demonstrate symptoms of hypervigilance and even paranoia, that are likely to be mediated by the dopamine system.

The opioid system may also be involved in PTSD, with endogenous opioids being released during trauma in order to act as "internal pain-killers".  Again there is evidence for sensitisation of this system, with less intense shock required for subsequent analgesia.  Interestingly, opioid substances of abuse are often favoured by patients with PTSD.  In the research setting, the opioid antagonist naloxone has been reported to reverse the analgesia induced by exposure to combat films.

Although increased release of cortisol might be expected in PTSD patients, recent studies in fact demonstrate hypocortisolaemia.  Furthermore, on the dexamethasone suppression test (DST), there is hypersuppression of cortisol.  Perhaps in PTSD increased secretion of corticotropin-releasing factor (CRF) leads to enhanced negative feedback (increased glucocorticoid receptors) and subsequent dampening of response to stress (low baseline cortisol, cortisol hypersuppression after dexamethasone).  Once again, the system can be conceived as overly responsive (sensitised) rather than as adapted.

A number of studies also suggest serotonergic involvement in PTSD.  In studies of fear conditioning, for example, serotonin appears to play an important role (Hensman et al., 1991).  Furthermore, serotonin is involved in stress-induced corticosteroid release (Joseph and Kennell, 1983).  In clinical studies of PTSD, paroxetine binding sites were reduced but had greater affinity in PTSD compared with normal participants, and there was a relationship between pre-treatment paroxetine binding and clinical response to fluoxetine treatment (Arora et al., 1993; Fichtner et al., 1994).   Also, m-chlorophenylpiperazine (m-CPP), a serotonin agonist, provoked PTSD symptoms in patients with this disorder (Southwick et al., 1995).  Finally, clinical overlaps between PTSD and depression, anxiety, impulsivity and aggression also suggest that serotonergic agents deserve study in the treatment of this disorder (Davis et al., 1997).

The idea that PTSD does not involve the classical or normal stress response, but rather involves abnormal neurobiological processes, is also consistent with clinical knowledge.  PTSD is in many ways a unique syndrome, so it is not altogether surprising for example that hypersuppression on the DST in this disorder contrasts with classical non-suppression in depression.  Furthermore, neurobiological sensitisation is consistent with our clinical understanding of the adverse effects of early life events on subsequent responses to trauma.

It may already be clinically useful to try and relate some of the neurobiological dysfunctions found in PTSD to the different symptom clusters found in this disorder (Charney et al., 1993).  Thus noradrenergic sensitisation presumably lies at the basis of hyperarousal symptoms.  Opioid dysfunction may underlie some of the numbing symptoms seen in PTSD.  Dopamine dysfunction may mediate symptoms of hypervigilance and paranoia.  Cortisol mediated damage to the hippocampus may underpin problems in memory.  Such a schema, although undoubtedly overly simplistic, may also lead to a heuristic approach to the pharmacotherapy of PTSD (Charney et al., 1993).  For example, tricyclic antidepressants which act on the noradrenergic system may be useful in reversing hyperarousal symptoms.  Similarly, clonidine, an alpha-2-agonist which results in decreased noradrenergic function may be useful in PTSD.  Dopamine blockers may be useful for patients with psychotic or near-psychotic symptoms.  Opioid blockers are not well studied in PTSD, but may turn out to be useful in the future.  Serotonin interacts with a range of other neurotransmitters, perhaps accounting in part for the promising effects of the serotonin reuptake inhibitors in PTSD.

 

Last updated: 20.12.2011

 

 

 

 

   Feedback        Site map         Help         Home         Editorial board         Disclaimer