Attenuation of the Effects of Corticosteroids on Declarative Memory with Lamotrigine
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Neuropsychopharmacology (2008) 33, 2376–2383 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Attenuation of the Effects of Corticosteroids on Declarative Memory with Lamotrigine ,1 1 1 2 1 E Sherwood Brown* , Justin Wolfshohl , Mujeeb U Shad , Miguel Vazquez and I Julian Osuji 1 2 Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n ¼ 16 for lamotrigine, n ¼ 12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n ¼ 9 for lamotrigine, n ¼ 11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n ¼ 8, missing data or dropouts n ¼ 8) compared to the placebo group (n ¼ 11, dropout n ¼ 1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n ¼ 7) and placebo (n ¼ 7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern. Neuropsychopharmacology (2008) 33, 2376–2383; doi:10.1038/sj.npp.1301627; published online 14 November 2007 Keywords: corticosteroids; lamotrigine; memory; hippocampus INTRODUCTION the effects of corticosteroids on the human hippocampus is challenging since humans cannot ethically be administered An extensive literature suggests that stress or excessive corticosteroids for extended periods of time. Therefore, a corticosteroid exposure is associated with changes in much smaller human literature on the effects of corticos- memory and hippocampal structure in animals (Magarin˜os teroids on the hippocampus is available. Acute administra- et al, 1997; Vyas et al, 2002; Uno et al, 1989, 1994; Sapolsky tion of exogenous corticosteroids in humans is associated et al, 1990; Lupien and McEwen, 1997). Leverenz et al with decline in declarative memory performance (New- (1999) did not find overall between-group differences in comer et al, 1999; de Quervain et al, 2000; Brown et al, 2006; total hippocampal or subfield volumes, neuronal number, Bender et al, 1988). Patients with Cushing’s disease, and or density in older macaques given oral hydrocortisone for cortisol elevations secondary to ACTH-producing pituitary 12 months. However, they found a strong negative tumors, have memory impairment (Mauri et al, 1993; correlation between cerebrospinal fluid (CSF) cortisol levels Starkman and Schteingart, 1981) and hippocampal atrophy and hippocampal volume (r ¼ 0.83, p 0.05) (Leverenz et al, p (Starkman et al, 1992) that are at least partially reversible a 2003). In animals, agents that decrease glutamate release or mean of 17 months after surgery to normalize cortisol levels enhance serotonin reuptake attenuate the effects of (Starkman et al, 1999, 2003). corticosteroids on the hippocampus (Magarin˜os and We reported that patients receiving long-term corticos- McEwen, 1995; Magarin˜os et al, 1996, 1999; Luine et al, teroid therapy had significantly poorer declarative memory 1994; Conrad et al, 1996; Watanabe et al, 1992). Examining performance, lower temporal lobe levels of N-acetyl aspartate (NAA), and smaller hippocampal volumes than *Correspondence: Dr ES Brown, Department of Psychiatry, University controls with similar medical histories not taking corticos- of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, teroids (Brown et al, 2004). However, another report did not Dallas, TX 75390-8849, USA, Tel: + 1 214 645-6950, Fax: + 1 214 find a reduction in NAA levels in patients taking 645-6951, E-mail: [email protected] corticosteroids (Khiat et al, 2001), and no changes in Received 16 May 2007; accepted 21 September 2007 hippocampal volume (Hajek et al, 2006) or post-mortem Effects of corticosteroids on declarative memory ES Brown et al 2377 histology (Lucassen et al, 2001) were found during Diagnostic and Declarative Memory Assessment corticosteroid exposure that was of much shorter duration A structured clinical interview for DSM-IV (SCID-CV) (First than in our report (Brown et al, 2004). et al, 1995) was administered at baseline to assess past and We previously reported significant improvement in current psychiatric diagnoses that were exclusionary. The declarative memory in corticosteroid-treated patients given Rey Auditory Verbal Learning Test (RAVLT) (Schmidt, open-label lamotrigine (Brown et al, 2003), an antiseizure and mood-stabilizing medication that inhibits glutamate 1996) was administered at baseline and weeks 12 and 24 follow-up, by a blinded staff member, with extensive release through modulation of high voltage-activated training and experience to assess declarative memory, using calcium currents (Stefani et al, 1997; Pisani et al, 2004; alternate versions (administered in a randomized order) to Wang et al, 2001) and sodium channels (Stefani et al, 1997; minimize practice or learning effects. The RAVLT consists Rogawski and Loscher, 2004; Sitges et al, 2007; Remy et al, of 15 nouns read aloud for five consecutive trials with each 2003). In this report we examined the impact of 24 weeks of trial followed by a free-recall trial. The total score is the total randomized, double-blind, placebo-controlled treatment number of words recalled through the five trials. Normative with lamotrigine on declarative memory in patients RAVLT T-scores controlling for age are reported. receiving prescription corticosteroids as the primary aim. A secondary aim was to examine whether between-group differences in hippocampal volume could be detected MRI and Procedures following 24 weeks of lamotrigine therapy. Structural and functional magnetic resonance (MR) images of the brain were obtained at baseline and week 24 follow- up visits. MR images were acquired on a General Electric METHODS Horizon LX NV/i 1.5 Tesla scanner (General Electric Medical Systems, Milwaukee, WI) using the standard GE Participants and Study Medication quadrature birdcage RF head coil. To avoid large head A total of 28 medically stable outpatients receiving chronic motions, each subject’s head was immobilized with tightly oral corticosteroid therapy participated in a 24-week fitting foam padding and a head strap that was fastened randomized, double-blind, placebo-controlled trial of lamo- across the forehead. High-resolution T1 images of the entire trigine. The enrollment period was from August 2002 brain (3D Spoiled Grass (SPGR) pulse sequence: through March 2005 with the final week-24 assessment in TR ¼ 40 ms; TE ¼ 5 ms; flip angle ¼ 401; matrix ¼ 256 Â 256; October 2005. Participants were enrolled from clinics in the FOV ¼ 24; PFOV ¼ 0.75, NEX ¼ 1; slice thickness ¼ 1.7 mm) UT Southwestern Medical Center that treat patients with were acquired during the same scan session for each chronic oral corticosteroid therapy. Assessments and participant. interventions were conducted at the Psychoneuroendocrine Research Program clinic at UT Southwestern. Inclusion Structural MRI Volumetric Analysis criteria were age of 18–65 years and corticosteroid therapy of at least 7.5 mg of prednisone equivalents daily for at least Anatomical measurements were conducted by two trained 6 months. Exclusion criteria were drug or alcohol abuse or and reliable raters and were supervised by one of the dependence, illnesses associated with hippocampal atrophy authors (MUS), who, following training at Dr MS Kesha- or with significant CNS involvement (seizures, closed head van’s laboratory at the University of Pittsburgh, has injury with loss of consciousness, brain tumors, multiple conducted structural imaging analysis at the University of sclerosis), history of a depressive disorder not related to Pittsburgh and UT Southwestern since 2000 (Shad et al, corticosteroid therapy, bipolar disorder, schizophrenia, or 2004, 2006). BRAINS2 software (Magnotta et al, 2002) was posttraumatic stress disorder on a structured clinical used to conduct the measurements. Both raters were blind interview, mental retardation, dementia or other severe to participant identity, study group assignment, and clinical cognitive impairment, pregnant or nursing women, severe data. The scans were analyzed in pairs (baseline, week 24) or life-threatening medical illness which would make for each participant with the rater unaware of the