Peter O'Donnell
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New perspectives are opening up for pharmacological treatment of post-traumatic stress disorder (PTSD), according to the European
Medicines Agency (EMEA). So far, drug treatment options for this severe and prevalent pathology have been limited.
Serotoninergic agents, tricyclic antidepressants, mood stabilizers, adrenergic inhibiting agents, antipsychotics, and benzodiazepines
have all been proposed for controlling symptoms, but to date only sertraline and paroxetine have been authorized for treatment.
But the prospects are now "potentially promising," says EMEA, presenting a new guideline on the planning of studies in this
area.
As the agency points out, numerous biological dysregulations are being identified among PTSD patients, covering the opioid,
glutaminergic, noradrenergic, and serotoninergic neurotransmitter systems, resulting in neuro-endocrinological disturbances
and physiological symptoms. Neuroimaging studies in PTSD show alterations in brain function in the medial prefrontal cortex,
hippocampus, thalamus, amygdala, anterior cingulated gyrus, temporal cortex, and visual association cortex.
However, advances in understanding the disorder "also raise the question of how to deal with the complexity," the agency observes.
The clinical response to a medicinal product could depend on its pharmacological properties, on the time to treatment after
exposure to the trauma, on the type of trauma, and on predominant symptoms. Further challenges include the high prevalence
of co-morbid depression, substance abuse, and anxiety disorders and the diagnostic criteria to be used. Hence the guideline.In designing studies, says the agency, patients should be diagnosed by an experienced psychiatrist according to an acknowledged
classification system, and confirmed by a structured interview. The use of a severity rating scale alone is insufficient and
is not equivalent to a diagnosis. But the severity of the disorder should be assessed, and a minimum severity for inclusion
should be defined and justified.
Further parameters, such as duration of the disorder, whether onset was immediate or delayed, presence/absence of childhood
trauma-neglect-abuse, and the type of precipitating event (i.e., combat, abuse, natural disaster, whether physical injury
was involved, and whether the event had an acute or a chronic nature) should be ascertained and specified in the inclusion
criteria. Patients with a current or recent history of major depression should be excluded from the study, as should patients
with recent or concurrent psychiatric co-morbidities or patients receiving specific psychotherapy.
Efficacy assessment
In assessing efficacy, the primary endpoint should be based on an established severity scale that captures the core symptoms
and has known and acceptable psychometric properties.
The scale needs to be validated in advance in the target population. Improvement of symptomatology should be documented as
a difference between baseline and post-treatment score, and also expressed as the proportion of responders and/or remitters.
Criteria for response and remission should be outlined and justified in the protocol. Results should be discussed in terms
of both clinical and statistical significance, and improvement should be demonstrated on all core symptom clusters. Global
assessment or other scales addressing issues such as social functioning may be used as secondary efficacy endpoints in confirmatory
studies.
In the strategy for clinical trials, exploratory trials can make use of pharmacodynamic tests to support the working mechanism
of the test product, by demonstrating effects on dysregulated neurotransmitter systems in brain areas that are hypothesized
to be involved.
The usual pharmacokinetic studies should be performed, and in dose-response studies, plasma levels may be studied. Controlled,
parallel, fixed-dose studies, using at least three dosages are needed to establish the effective dose range as well as the
optimal dose, based on efficacy and tolerability. The agency recommends the addition of a placebo as well as an active comparator
to these studies.
In therapeutic confirmatory studies, parallel, double blind, randomized placebo controlled studies are necessary to establish
acute efficacy. The duration of these studies should be derived from pilot studies indicating the time necessary for achieving
a stable effect. Comparison with a standard product already registered for the treatment of PTSD as a third study arm is recommended
to make it possible to put the size of the effect into context in relation to standard treatment. The dose and the comparator
should be justified.
When estimating the effect on PTSD, it is necessary to control for the effect of treatment on depressive symptoms in the statistical
analysis. The effect should be robust when residual depression symptoms are controlled for.
Since PTSD is a chronic condition, long-term efficacy and safety should be demonstrated. A possible design for demonstrating
maintenance of effect over longer durations is a randomized withdrawal study. The duration of the long-term studies should
be justified. Efficacy in long-term controlled studies is usually expressed as the proportion of patients worsening (relapsing)
and/or time to this event. Both efficacy criteria are of interest and should be presented. Worsening and relapse have to be
defined in the protocol and should reflect clinical relevant increase of symptoms, scored on a validated rating scale at one
or more visits.
