Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder
Introduction
A wide range of evidence from animal studies has demonstrated memory deficits and damage to the hippocampus, a brain area that plays a critical role in learning and memory, after exposure to stress Lupien and Lepage, 2001, Sapolsky, 1996, Vermetten and Bremner, 2002. Several mechanisms have been proposed for this finding, including high levels of glucocorticoids released during stress McEwen et al., 1992, Sapolsky et al., 1990, increased production of corticotrophin-releasing factor (Brunson et al 2001), increased release of excitatory amino acids Moghaddam, 2002, Moghaddam et al., 1994, inhibition of neurogenesis (Gould et al 1997), and/or stress-related inhibition of brain-derived neurotrophic factor (BDNF) Nibuya et al., 1995, Smith et al., 1995. Treatment with selective serotonin reuptake inhibitors (SSRIs) has demonstrated reversal of hippocampal atrophy and promotion of neurogenesis Duman et al., 2001, Malberg et al., 2000.
Adults with posttraumatic stress disorder (PTSD) related to combat exposure or childhood physical or sexual abuse have been shown to have reduced hippocampal size on magnetic resonance imaging (MRI) when compared with healthy or trauma control subjects Bremner et al., 1995a, Bremner et al., 1997, Gurvits et al., 1996, Stein et al., 1997, Villarreal et al., 2002) Trauma at different stages of life (early childhood abuse as well as trauma in later life [e.g., due to combat]) has been thought to influence hippocampal volume. Several clinical studies have also reported alterations in learning and memory in patients with PTSD, which are consistent with both deficits in encoding on explicit memory tasks and deficits in retrieval, as well as enhanced encoding or retrieval for specific trauma-related material Andrews et al., 2000, Buckley et al., 2000, Gilbertson et al., 2001, Pitman, 1989, Roca and Freeman, 2001, Vasterling et al., 1998, Wolfe and Schlesinger, 1997. The majority of these studies found deficits in verbal memory, with a relative absence of deficits in tasks of attention or visuospatial memory. The alterations varied from self-reported difficulties in memory (Thygesen et al 1970) to impairments of verbal declarative memory Bremner et al., 1993a, Bremner et al., 1995b, Gilbertson et al., 2001, Jenkins et al., 1998, Moradi et al., 1999, Sutker et al., 1991, Uddo et al., 1993, Yehuda et al., 1995). These studies, which involved heterogenous groups of trauma populations and comorbidity status, all reported specific deficits in explicit memory function in PTSD (with no change in intelligence quotient). Some studies report that the memory impairments could not be accounted for by attentional disturbances or intellectual functioning Gilbertson et al., 2001, Vasterling et al., 2002; others do report evidence of attentional and/or executive dysfunction in PTSD (Semple et al 1996). Some studies did not report specificity of verbal declarative memory deficits in PTSD Crowell et al., 2002, Dalton and Pederson, 1989, Zalewski et al., 1994.
Studies in patients with epilepsy have shown a correlation between deficits in verbal declarative memory and decreased density of neurons in the hippocampus (Sass et al 1990). Patients with Cushing's disease (in which there are abnormally high levels of cortisol in the plasma) had deficits in verbal declarative memory and smaller hippocampal volume; smaller hippocampal volume was correlated with elevations in plasma cortisol levels. Treatment of hypercortisolemia was associated with a significant increase in hippocampal volume and improvement in verbal declarative memory function, suggesting that hippocampal damage is reversible Bourdeau et al., 2002, Starkman et al., 1999, Starkman et al., 2003.
Neurons within the hippocampus were found to be unique within the brain in showing the capacity to regenerate themselves (Gould et al 1998). Studies in animals have demonstrated that several agents (e.g., phenytoin, tianeptine, dehydroepiandrosterone, and the SSRI fluoxetine) might block or modulate the effects of stress on the hippocampus Czeh et al., 2001, Malberg et al., 2000, Manev et al., 2001, Watanabe et al., 1992. Selective serotonin reuptake inhibitors also promote neurogenesis in the hippocampus through a regulation of BDNF and cyclic adenosine monophosphate (cAMP), with long-term effects on brain function (Duman et al 2001). In these studies it was chronic, but not acute, administration of these drugs that induced the changes in morphology (Nibuya et al 1996).
Several prior studies have demonstrated the efficacy of paroxetine on clinical measures of PTSD Marshall et al., 1998, Marshall et al., 2001, Tucker et al., 2001, but no studies have yet looked at the effects of paroxetine—or any medication, for that matter—on verbal declarative memory or other cognitive functions in PTSD. An important question related to the effects of stress on the hippocampus was whether these memory deficits and the hippocampal atrophy in traumatized patients with PTSD are reversible. The purpose of this study was, therefore, to assess the effects of treatment with the SSRI paroxetine on these parameters. We hypothesized that patients who responded to treatment with paroxetine would also demonstrate an improvement in declarative memory performance and show increased hippocampal volume.
Section snippets
Subjects
Patients with symptoms of PTSD were recruited by advertisements in newspapers and flyers. Some patients in this study were part of a national double-blind trial of paroxetine compared with placebo in PTSD. After 12 weeks of participation in the study, subjects were offered participation in an extension phase of 9 months open-label treatment of 10–50 mg paroxetine per day. After initial phone screening, a total of 46 patients were invited to participate in the study. Eighteen patients did not
Results
Paroxetine treatment resulted in a mean 54% reduction (85.3% [SD 22.45%] to 38.6% [SD 28.2%]) in PTSD symptoms as measured with mean changes from baseline on the CAPS total score [t(1,22) = 7.10, p = .000] among study completers. Improvement was equally strong on all symptom cluster scores (re-experiencing, avoidance/numbing, hyperarousal) (Figure 1).
Treatment also resulted in significant improvements in verbal declarative memory, as measured with the WMS-R paragraph recall, for delayed recall
Discussion
Our findings of clinical efficacy of paroxetine are in line with earlier reports of open-label Marshall et al., 1998, Smajkic et al., 2001 and placebo-controlled studies Marshall et al., 2001, Tucker et al., 2001 that showed a similar drop in CAPS scores in PTSD. Treatment led to a significant improvement in verbal declarative memory function. The difference in immediate and delayed memory performance, which is best reflected by the percent retention score, improved significantly for verbal
Acknowledgements
This work was supported by National Institute of Mental Health ROI MH56120, by a grant from GlaxoSmithKline, by the National Center for Posttraumatic Stress Disorder, and a Veterans Affairs Career Development Award to JDB.
We thank Christian Schmahl, M.D., and Sajid Siddiq, M.D., for expert assistance in image processing and analysis; Heather Douglas Palumberi, M.A., Tammy Rowe, B.A., and Jacque Piscatelli, R.N., for assistance in patient recruitment and assessment; and Terry Hickey, R.T.N.M.,
References (68)
- et al.
Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report
Biol Psychiatry
(1997) - et al.
Information processing and PTSDA review of the empirical literature
Clin Psychol Rev
(2000) - et al.
Regulation of adult neurogenesis by antidepressant treatment
Neuropsychopharmacology
(2001) - et al.
Effect of chronic antidepressant treatment on transcription factor binding activity in rat hippocampus and frontal cortex
Prog Neuropsychopharmacol Biol Psychiatry
(1998) - et al.
Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder
Biol Psychiatry
(1996) - et al.
Longitudinal study of brain morphology in first episode schizophrenia
Biol Psychiatry
(2001) - et al.
Stress, memory, and the hippocampusCan't live with it, can't live without it
Behav Brain Res
(2001) - et al.
Fluoxetine increases the content of neurotrophic protein S100beta in the rat hippocampus
Eur J Pharmacol
(2001) - et al.
Paradoxical effects of adrenal steroids on the brainProtection versus degeneration
Biol Psychiatry
(1992) Stress activation of glutamate neurotransmission in the prefrontal cortexImplications for dopamine-associated psychiatric disorders
Biol Psychiatry
(2002)
Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate
Brain Res
Post-traumatic stress disorder, hormones, and memory
Biol Psychiatry
AnalyzeA comprehensive, operator-interactive software package for multidimensional medical image display and analysis
Comput Med Imaging Graph
Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder
Psychiatry Res
Attention and regional cerebral blood flow in posttraumatic stress disorder patients with substance abuse histories
Psychiatry Res
Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease
Biol Psychiatry
Improvement in learning associated with increase in hippocampal formation volume
Biol Psychiatry
Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder
Biol Psychiatry
The timing, triggers and qualities of recovered memories in therapy
Br J Clin Psychol
The development of a Clinician-Administered PTSD Scale
J Trauma Stress
Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism
J Clin Endocrinol Metab
MRI-based measurement of hippocampal volume in patients with combat- related posttraumatic stress disorder
Am J Psychiatry
Deficits in short-term memory in adult survivors of childhood abuse
Psychiatry Res
Deficits in short-term memory in posttraumatic stress disorder
Am J Psychiatry
Childhood physical abuse in combat-related posttraumatic stress disorder
Am J Psychiatry
Development and preliminary psychometric properties of an instrument for the measurement of childhood traumaThe Early Trauma Inventory
Depress Anxiety
Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress
Proc Natl Acad Sci U S A
Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs
Am J Psychiatry
Neuropsychological findings in combat-related posttraumatic stress disorder
Clin Neuropsychol
Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine
Proc Natl Acad Sci U S A
Effects of post-traumatic stress disorder on neuropsychological test performance
Int J Clin Neuropsychol
Multivariate assessment of explicit memory function in combat veterans with posttraumatic stress disorder
J Trauma Stress
Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma
Nat Neurosci
Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation
J Neurosci
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