Preface Posttraumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known, viz., an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness, or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular, and molecular levels. The present review attempts to present the current state of this understanding, based upon psychophysiological, structural and functional neuroimaging, endocrinological, genetic, and molecular biological studies in humans and in animal models.

We recently reported that f luoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO) without altering the brain content of other neurosteroids. ALLO (3␣5␣ and 3␣5␤ isomers) binds with high affinity to various ␥-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal f luid (CSF) before and 8-10 weeks after treatment with f luoxetine or f luvoxamine in 15 patients with unipolar major depression. The concentration of ALLO (Ϸ40 fmol͞ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, f luoxetine or f luvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r ‫؍‬ 0.58; P < 0.023; n ‫؍‬ 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after f luoxetine or f luvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of f luoxetine or f luvoxamine via its positive allosteric modulation of GABA type A receptors.Fluoxetine, fluvoxamine, and other selective 5HT reuptake inhibitors (SSRIs) have a spectrum of therapeutic actions that is broader than that of the monoamine oxidase inhibitors or the tricyclic imipramine-like antidepressants (1-5). Because several lines of evidence indicate that the action of various antidepressant classes is related to an enhancement of serotonin (5HT)-mediated neurotransmission and SSRIs are more selective in inhibiting 5HT reuptake than tricyclic antidepressants (6), it is possible that the therapeutic properties that are exclusively elicited by SSRIs may not depend only on 5HT neurotransmission for their action.We have recently reported that fluoxetine and paroxetine, two SSRIs, but not imipramine, when administered to rats, increase the steady-state brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO), without altering the brain content of other neurosteroids (7) (for chemical structure and biosynthetic pathways of neurosteroids, see Fig.

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Exposure to mild stress is known to activate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) metabolism in the anteromedial prefrontal cortex (m-PFC). Neuroanatomical site(s) providing afferent control of the stress activation of the m-PFC monoaminergic systems is at present unknown. The present study used a conditioned stress model in which rats were trained to fear a substartle-threshold tone paired previously with footshock and assessed for behavioral, neuroendocrine, and neurochemical stress responses. Bilateral NMDA-induced excitotoxic lesioning of the basolateral and central nuclei of the amygdala was performed before or after training. Pretraining amygdala lesions blocked stress-induced freezing behavior, ultrasonic vocalizations, adrenocortical activation, and dopaminergic metabolic activation in the m-PFC. Post-training amygdala lesions blocked stress-induced m-PFC DA, 5-HT, and NE metabolic activation. Post-training amygdala lesions also blocked stress-induced freezing and defecation, and greatly attenuated adrenocortical activation. These data provide evidence of amygdalar control of stress-induced metabolic activation of the monoaminergic systems in the m-PFC, as well as amygdalar integration of behavioral and neuroendocrine components of the rat stress response. These results are discussed in terms of possible relevance to stress-induced exacerbation of schizophrenic symptoms and the pathophysiology of posttraumatic stress disorder.

Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed.

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