Journal of Traumatic Stress June 2014, 27, 291–298
Verbal Learning Deficits in Posttraumatic Stress Disorder and Depression Diane L. Scheiner,1 John Keilp,2 Monica Rivera Mindt,1 Ainsley K. Burke,2 Maria A. Oquendo,2 and J. John Mann2 2
1 Department of Psychology, Fordham University, Bronx, New York, USA Department of Psychiatry, Columbia University, and Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York, USA
Verbal learning and memory deficits are frequently reported in posttraumatic stress disorder (PTSD), but may be a product of its psychiatric comorbidities, especially major depressive disorder (MDD). To evaluate this hypothesis, 25 medication-free patients with PTSD and comorbid MDD were compared to 148 medication-free patients with equally severe MDD alone and to 96 nonpatients on a measure of verbal learning and memory. Additional measures of attention, working memory, and executive function were administered to evaluate their contribution to verbal memory impairment. Patients with comorbid PTSD and MDD demonstrated the greatest deficit in verbal learning compared to both MDD patients and nonpatients (omnibus effect sizes ranged d = 0.41 to 0.50), one that was not accounted for by other cognitive deficits. Findings suggest that a current diagnosis of PTSD makes a contribution to verbal learning deficits beyond the effect of depression alone.
Verbal learning deficits are a common neurocognitive finding associated with posttraumatic stress disorder (PTSD), which may have adverse implications for diagnosed individuals’ everyday functioning and treatment outcomes (Geuze, Vermetten, de Kloet, Hijman, & Westenberg, 2009; Wild & Gur, 2008). Recent meta-analyses demonstrated impairment in verbal learning in adults with PTSD compared to adults exposed to trauma who did not develop PTSD, and nonexposed healthy controls; a finding that is independent of a number of potential confounds, including comorbid substance abuse and history of head injury (Brewin, Kleiner, Vasterling, & Field, 2007; Johnsen & Asbjornsen, 2008). The pathophysiology of these deficits remains unclear. They have been associated with functional abnormalities of the hypothalamic–pituitary– adrenal axis, heightened amygdalar reactivity, and hippocampal atrophy (all of which are implicated in disruptions of normal learning and memory function: see Bremner, 2006; Francati,
Vermetten, & Bremner, 2007; Shin, Rauch, & Pitman, 2006; Zoladz & Diamond, 2013 for reviews). Such pathophysiologic markers are nonspecific, however, and overlap with those of other neuropsychiatric disorders, including major depression (MDD; Conrad, 2008; Maletic et al., 2007; Strohle & Holsboer, 2003). MDD is also the most frequently diagnosed mood disorder in samples of those with PTSD (Breslau, 2002). Although research shows less evidence for learning and memory deficits in adults with depression (Castaneda et al., 2008; Wang et al., 2006), studies report neurocognitive findings in attention, information processing, and executive functions, with implications for poorer new learning and memory performance (e.g., Den Hartog, Derix, Van Bemmel, Kremer, & Jolles, 2003; Harvey et al., 2004; Keilp, Gorlyn, Oquendo, Burke, & Mann, 2008; Keilp et al., 2001). Given the overlap of MDD and PTSD diagnostic criteria (Brady, Killeen, Brewerton, & Lucerini, 2000) and these disorders’ common hypothesized neurobiological substrates, it is unclear to what extent comorbidities account for neurocognitive deficits observed in PTSD samples. To date, verbal learning deficits related to PTSD have most often been reported in the context of active, concurrent psychiatric illness and substance use. Although PTSD effects were found in some studies adjusting for comorbid symptom severity (e.g., Gilbertson, Gurvits, Lasko, Orr, & Pitman, 2001; Golier et al., 2002; Samuelson et al., 2006), those excluding comorbidities often reported negligible—or no—influence of PTSD on memory task performance (e.g., Crowell, Kieffer, Siders, & Vanderploeg, 2002; Neylan et al., 2004). Johnsen, Kanagaratnam, and Asbjornsen (2008) found that self-reported
This work was supported by the National Institute of Mental Health grants MH-62155 and Conte Center for the Neurobiology of Mental Disorders (5 P50 MH-62185). The authors wish to thank Nilima Ramaswamy, Mary Russell, Benjamin Hamburger, and Simone LeBlanc of the New York State Psychiatric Institute, for their assistance in the collection of study data. We also express our appreciation to each of our volunteer research participants. Correspondence concerning this article should be addressed to Diane Scheiner, Psychology Department (116B), VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Building 256, Room 204, 11301 Wilshire Blvd., Los Angeles, CA 90073. E-mail: [email protected] C 2014 International Society for Traumatic Stress Studies. View Copyright this article online at wileyonlinelibrary.com DOI: 10.1002/jts.21921
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Scheiner et al.
depressive symptoms explained a significant portion of the variance of word list learning in a refugee group diagnosed with PTSD, compared to the performance of a comparable group of participants exposed to trauma, but who did not manifest PTSD. In a second study in which all participants diagnosed with PTSD had a comorbid diagnosis of MDD (Johnsen & Asbjornsen, 2009), verbal list learning differences between experimental and control groups were eliminated by adjusting for depressive symptom severity. The authors concluded that verbal memory disturbance in PTSD was attributable to the severity of these comorbid depressive symptoms. The clinical complexity of PTSD contributes to a lack of consensus regarding why verbal learning deficits, in particular, are found in psychiatric syndromes associated with trauma. To date, it remains unanswered whether deficits in PTSD are in part (or entirely) attributable to depression, because studies have not systematically examined the concurrent contributions of these frequently co-occurring conditions. The current study built upon prior research by examining the independent impact of MDD, and the combined impact of PTSD and MDD, upon verbal learning and memory, permitting characterization of deficits observed in naturalistic (i.e., comorbid condition) PTSD samples. Specifically, the current study examined a sample of PTSD patients with comorbid MDD, compared to a sample of individuals with MDD of comparable severity without PTSD. We hypothesized that depression alone would not result in verbal learning deficits as severe as those among PTSD patients with comorbid MDD, using nonpatient control performance as a comparative benchmark. We also considered the influence of other neurocognitive functions on patient groups’ verbal learning. Because impoverished encoding (i.e., learning) is a significant contributor to subsequent recall failures in PTSD (Gilbertson et al., 2001; Vasterling et al., 2002), attention and working memory, as well as higher-order executive deficits, are often implicated in emergent learning difficulties. Therefore, we included measures of attention (continuous performance test), working memory (A not B reasoning task), and executive function (Wisconsin Card Sorting Test) in our assessment battery. Studies suggest that problems of attention are insufficient to explain verbal learning deficits in PTSD (Johnsen et al., 2008; Yehuda, Golier, Halligan, & Harvey, 2004; Yehuda, Golier, Tischler, Stavitsky, & Harvey, 2005), but additional research is needed to evaluate the effect of these other frequent intercurrent deficits. We expected that performance on measures of attention, working memory, and executive function would contribute to, but not entirely explain, differences between patient groups.
Method
[APA], 2000) for current PTSD and MDD (comorbid PTSD with MDD group), 148 patients with current MDD but no lifetime history of PTSD (MDD group), and 94 nonpatient comparison participants (nonpatient group). All participants were free of neurological disease and gross organic brain dysfunction by clinical history and examination, had an estimated IQ > 80, and were younger than 60 years of age. Patients were medication-free or washed out of medications for participation in associated biological studies at least 2 weeks prior to their neurocognitive assessment (6 weeks if on fluoxetine). Characteristics of the study groups are presented in Table 1. Nonpatients were younger than both patient groups, and there was a greater proportion of women in the comorbid PTSD with MDD group compared to nonpatients and patients with MDD alone. Across the entire sample, 62.2% self-identified as nonHispanic White, 18.0% as Black, 8.2% as Hispanic, and 11.6% as Asian. Non-Hispanic White participants composed the majority of both patient groups. By contrast, Black and Asian participants were disproportionately represented in the nonpatient group. The percentage of Hispanic participants in all three groups was roughly equivalent. Pairwise chi-square analyses revealed the racial ethnic breakdown of the nonpatient group differed significantly only from that of the MDD group. There was no difference between the MDD and comorbid PTSD with MDD groups in terms of racial ethnic composition (all p values ns). By contrast, all three groups were similar in terms of their education level, estimated premorbid verbal intelligence based on the Wechsler Adult Intelligence Scale–Third Edition (WAISIII; Wechsler, 1997) Vocabulary subtest scaled score, and percentage of participants who were native English speakers. Participants in both patient groups were currently depressed using a 24-item Hamilton Rating Scale for Depression (Hamilton, 1960) score ࣙ 16 at time of recruitment, had no history of other severe mental illness (i.e., schizophrenia, other psychotic disorders, bipolar disorder) and no current substance abuse or dependence diagnosis (past abuse or dependence more than 6 months prior was allowed). For participants in the comorbid PTSD with MDD group, civilian (i.e., noncombat) physical and/or sexual abuse histories were overly represented as the traumatic etiology for PTSD diagnosis (80.0% of comorbid group patients). Of those with lifetime civilian physical and/or sexual abuse histories, 90.0% experienced their abuse prior to age 15. Comorbid PTSD with MDD patients were also more likely to meet criteria for a current diagnosis of panic disorder, but patient groups were otherwise similar in rates of other concurrent psychiatric conditions (e.g., borderline personality disorder, prior history of substance and alcohol use disorders). Nonpatients had no current or past history of Axis I or Axis II disorders (past adjustment disorders were not exclusionary).
Participants Participants included 25 patients meeting criteria according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association
Procedure Participants were recruited via New York State Psychiatric Institute Institutional Review Board-approved advertisements
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
293
Verbal Learning Deficits in PTSD and MDD
Table 1 Demographic, Clinical Characteristics, and Differences Across Three Study Groups Nonpatient (n = 94)
MDD (n = 148)
PTSD with MDD (n = 25)
Variable
M or n
SD or %
M or n
SD or %
M or n
SD or %
p
Age (years) Education (years) Vocabulary (ss) Sex (women) Race ethnicity Non-Hispanic White Black Hispanic Asian Native English speakers Ham-D total score BDI total sore GAF score Age MDD onset Lifetime depressive episodes Dysthymia Panic disorder Social phobia Generalized anxiety Obsessive–compulsive Borderline personality Any past substance use disorder Past alcohol abuse Past alcohol dependency
31.40 15.91 13.87 41
10.06 2.15 3.14 43.6
37.30 15.81 13.54 78
10.68 2.38 2.66 52.7
35.32 14.76 12.48 22
10.32 2.42 3.25 88.0
Verbal Learning Deficits in Posttraumatic Stress Disorder and Depression Diane L. Scheiner,1 John Keilp,2 Monica Rivera Mindt,1 Ainsley K. Burke,2 Maria A. Oquendo,2 and J. John Mann2 2
1 Department of Psychology, Fordham University, Bronx, New York, USA Department of Psychiatry, Columbia University, and Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, New York, USA
Verbal learning and memory deficits are frequently reported in posttraumatic stress disorder (PTSD), but may be a product of its psychiatric comorbidities, especially major depressive disorder (MDD). To evaluate this hypothesis, 25 medication-free patients with PTSD and comorbid MDD were compared to 148 medication-free patients with equally severe MDD alone and to 96 nonpatients on a measure of verbal learning and memory. Additional measures of attention, working memory, and executive function were administered to evaluate their contribution to verbal memory impairment. Patients with comorbid PTSD and MDD demonstrated the greatest deficit in verbal learning compared to both MDD patients and nonpatients (omnibus effect sizes ranged d = 0.41 to 0.50), one that was not accounted for by other cognitive deficits. Findings suggest that a current diagnosis of PTSD makes a contribution to verbal learning deficits beyond the effect of depression alone.
Verbal learning deficits are a common neurocognitive finding associated with posttraumatic stress disorder (PTSD), which may have adverse implications for diagnosed individuals’ everyday functioning and treatment outcomes (Geuze, Vermetten, de Kloet, Hijman, & Westenberg, 2009; Wild & Gur, 2008). Recent meta-analyses demonstrated impairment in verbal learning in adults with PTSD compared to adults exposed to trauma who did not develop PTSD, and nonexposed healthy controls; a finding that is independent of a number of potential confounds, including comorbid substance abuse and history of head injury (Brewin, Kleiner, Vasterling, & Field, 2007; Johnsen & Asbjornsen, 2008). The pathophysiology of these deficits remains unclear. They have been associated with functional abnormalities of the hypothalamic–pituitary– adrenal axis, heightened amygdalar reactivity, and hippocampal atrophy (all of which are implicated in disruptions of normal learning and memory function: see Bremner, 2006; Francati,
Vermetten, & Bremner, 2007; Shin, Rauch, & Pitman, 2006; Zoladz & Diamond, 2013 for reviews). Such pathophysiologic markers are nonspecific, however, and overlap with those of other neuropsychiatric disorders, including major depression (MDD; Conrad, 2008; Maletic et al., 2007; Strohle & Holsboer, 2003). MDD is also the most frequently diagnosed mood disorder in samples of those with PTSD (Breslau, 2002). Although research shows less evidence for learning and memory deficits in adults with depression (Castaneda et al., 2008; Wang et al., 2006), studies report neurocognitive findings in attention, information processing, and executive functions, with implications for poorer new learning and memory performance (e.g., Den Hartog, Derix, Van Bemmel, Kremer, & Jolles, 2003; Harvey et al., 2004; Keilp, Gorlyn, Oquendo, Burke, & Mann, 2008; Keilp et al., 2001). Given the overlap of MDD and PTSD diagnostic criteria (Brady, Killeen, Brewerton, & Lucerini, 2000) and these disorders’ common hypothesized neurobiological substrates, it is unclear to what extent comorbidities account for neurocognitive deficits observed in PTSD samples. To date, verbal learning deficits related to PTSD have most often been reported in the context of active, concurrent psychiatric illness and substance use. Although PTSD effects were found in some studies adjusting for comorbid symptom severity (e.g., Gilbertson, Gurvits, Lasko, Orr, & Pitman, 2001; Golier et al., 2002; Samuelson et al., 2006), those excluding comorbidities often reported negligible—or no—influence of PTSD on memory task performance (e.g., Crowell, Kieffer, Siders, & Vanderploeg, 2002; Neylan et al., 2004). Johnsen, Kanagaratnam, and Asbjornsen (2008) found that self-reported
This work was supported by the National Institute of Mental Health grants MH-62155 and Conte Center for the Neurobiology of Mental Disorders (5 P50 MH-62185). The authors wish to thank Nilima Ramaswamy, Mary Russell, Benjamin Hamburger, and Simone LeBlanc of the New York State Psychiatric Institute, for their assistance in the collection of study data. We also express our appreciation to each of our volunteer research participants. Correspondence concerning this article should be addressed to Diane Scheiner, Psychology Department (116B), VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Building 256, Room 204, 11301 Wilshire Blvd., Los Angeles, CA 90073. E-mail: [email protected] C 2014 International Society for Traumatic Stress Studies. View Copyright this article online at wileyonlinelibrary.com DOI: 10.1002/jts.21921
291
292
Scheiner et al.
depressive symptoms explained a significant portion of the variance of word list learning in a refugee group diagnosed with PTSD, compared to the performance of a comparable group of participants exposed to trauma, but who did not manifest PTSD. In a second study in which all participants diagnosed with PTSD had a comorbid diagnosis of MDD (Johnsen & Asbjornsen, 2009), verbal list learning differences between experimental and control groups were eliminated by adjusting for depressive symptom severity. The authors concluded that verbal memory disturbance in PTSD was attributable to the severity of these comorbid depressive symptoms. The clinical complexity of PTSD contributes to a lack of consensus regarding why verbal learning deficits, in particular, are found in psychiatric syndromes associated with trauma. To date, it remains unanswered whether deficits in PTSD are in part (or entirely) attributable to depression, because studies have not systematically examined the concurrent contributions of these frequently co-occurring conditions. The current study built upon prior research by examining the independent impact of MDD, and the combined impact of PTSD and MDD, upon verbal learning and memory, permitting characterization of deficits observed in naturalistic (i.e., comorbid condition) PTSD samples. Specifically, the current study examined a sample of PTSD patients with comorbid MDD, compared to a sample of individuals with MDD of comparable severity without PTSD. We hypothesized that depression alone would not result in verbal learning deficits as severe as those among PTSD patients with comorbid MDD, using nonpatient control performance as a comparative benchmark. We also considered the influence of other neurocognitive functions on patient groups’ verbal learning. Because impoverished encoding (i.e., learning) is a significant contributor to subsequent recall failures in PTSD (Gilbertson et al., 2001; Vasterling et al., 2002), attention and working memory, as well as higher-order executive deficits, are often implicated in emergent learning difficulties. Therefore, we included measures of attention (continuous performance test), working memory (A not B reasoning task), and executive function (Wisconsin Card Sorting Test) in our assessment battery. Studies suggest that problems of attention are insufficient to explain verbal learning deficits in PTSD (Johnsen et al., 2008; Yehuda, Golier, Halligan, & Harvey, 2004; Yehuda, Golier, Tischler, Stavitsky, & Harvey, 2005), but additional research is needed to evaluate the effect of these other frequent intercurrent deficits. We expected that performance on measures of attention, working memory, and executive function would contribute to, but not entirely explain, differences between patient groups.
Method
[APA], 2000) for current PTSD and MDD (comorbid PTSD with MDD group), 148 patients with current MDD but no lifetime history of PTSD (MDD group), and 94 nonpatient comparison participants (nonpatient group). All participants were free of neurological disease and gross organic brain dysfunction by clinical history and examination, had an estimated IQ > 80, and were younger than 60 years of age. Patients were medication-free or washed out of medications for participation in associated biological studies at least 2 weeks prior to their neurocognitive assessment (6 weeks if on fluoxetine). Characteristics of the study groups are presented in Table 1. Nonpatients were younger than both patient groups, and there was a greater proportion of women in the comorbid PTSD with MDD group compared to nonpatients and patients with MDD alone. Across the entire sample, 62.2% self-identified as nonHispanic White, 18.0% as Black, 8.2% as Hispanic, and 11.6% as Asian. Non-Hispanic White participants composed the majority of both patient groups. By contrast, Black and Asian participants were disproportionately represented in the nonpatient group. The percentage of Hispanic participants in all three groups was roughly equivalent. Pairwise chi-square analyses revealed the racial ethnic breakdown of the nonpatient group differed significantly only from that of the MDD group. There was no difference between the MDD and comorbid PTSD with MDD groups in terms of racial ethnic composition (all p values ns). By contrast, all three groups were similar in terms of their education level, estimated premorbid verbal intelligence based on the Wechsler Adult Intelligence Scale–Third Edition (WAISIII; Wechsler, 1997) Vocabulary subtest scaled score, and percentage of participants who were native English speakers. Participants in both patient groups were currently depressed using a 24-item Hamilton Rating Scale for Depression (Hamilton, 1960) score ࣙ 16 at time of recruitment, had no history of other severe mental illness (i.e., schizophrenia, other psychotic disorders, bipolar disorder) and no current substance abuse or dependence diagnosis (past abuse or dependence more than 6 months prior was allowed). For participants in the comorbid PTSD with MDD group, civilian (i.e., noncombat) physical and/or sexual abuse histories were overly represented as the traumatic etiology for PTSD diagnosis (80.0% of comorbid group patients). Of those with lifetime civilian physical and/or sexual abuse histories, 90.0% experienced their abuse prior to age 15. Comorbid PTSD with MDD patients were also more likely to meet criteria for a current diagnosis of panic disorder, but patient groups were otherwise similar in rates of other concurrent psychiatric conditions (e.g., borderline personality disorder, prior history of substance and alcohol use disorders). Nonpatients had no current or past history of Axis I or Axis II disorders (past adjustment disorders were not exclusionary).
Participants Participants included 25 patients meeting criteria according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association
Procedure Participants were recruited via New York State Psychiatric Institute Institutional Review Board-approved advertisements
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
293
Verbal Learning Deficits in PTSD and MDD
Table 1 Demographic, Clinical Characteristics, and Differences Across Three Study Groups Nonpatient (n = 94)
MDD (n = 148)
PTSD with MDD (n = 25)
Variable
M or n
SD or %
M or n
SD or %
M or n
SD or %
p
Age (years) Education (years) Vocabulary (ss) Sex (women) Race ethnicity Non-Hispanic White Black Hispanic Asian Native English speakers Ham-D total score BDI total sore GAF score Age MDD onset Lifetime depressive episodes Dysthymia Panic disorder Social phobia Generalized anxiety Obsessive–compulsive Borderline personality Any past substance use disorder Past alcohol abuse Past alcohol dependency
31.40 15.91 13.87 41
10.06 2.15 3.14 43.6
37.30 15.81 13.54 78
10.68 2.38 2.66 52.7
35.32 14.76 12.48 22
10.32 2.42 3.25 88.0
