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1.  A pilot randomized controlled trial with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom era veterans☆ 
Psychiatry research  2012;206(0):318-320.
Subthreshold posttraumatic stress disorder (PTSD) is associated with increased risk for suicidality, depression, and functional impairment. We thus conducted a small (N=12) pilot randomized controlled trial (RCT) with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) era veterans. Hospital Anxiety and Depression Scale (HADS) scores improved by 30.4% in the paroxetine group. Paroxetine may have promise for subthreshold PTSD.
doi:10.1016/j.psychres.2012.11.008
PMCID: PMC3788578  PMID: 23276723
PTSD; Subthreshold; Paroxetine
2.  Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia 
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
doi:10.1038/npp.2009.26
PMCID: PMC3427920  PMID: 19339966
schizophrenia; negative symptoms; cognitive symptoms; neurosteroid; pregnenolone; allopregnanolone
3.  Role of treatment alliance in the clinical management of bipolar disorder: Stronger alliances prospectively predict fewer manic symptoms 
Psychiatry Research  2006;145(2-3):215-223.
The strength of the treatment alliance between patients and their clinicians may play a unique role in the management of bipolar disorder. However, few empirical studies have examined the alliance in bipolar disorder or its effects on patient outcomes. This study investigates variables associated with a strong treatment alliance in bipolar disorder, and the prospective effects of treatment alliance on patients' mood symptoms and treatment attitudes. Participants were 58 longitudinally followed individuals with Bipolar I disorder. We found that alliance ratings covaried with depressive symptoms, such that alliance strength increased as depressive symptoms decreased, and stronger alliances were associated with more social support. Tests of temporal association indicated that stronger alliances predicted fewer manic symptoms 6 months later. Stronger alliances also predicted less negative attitudes about medication and less of a sense of stigma about bipolar disorder. Thus, a strong treatment alliance may help to reduce manic symptoms over time. It may be that a strong treatment alliance encourages patients' greater acceptance of bipolar disorder and psychopharmacological interventions, and thus contributes to improved medication adherence and clinical outcomes. Considered in sum, these findings suggest that the treatment alliance is an integral component of the long-term management of bipolar disorder.
doi:10.1016/j.psychres.2006.01.007
PMCID: PMC3400423  PMID: 17079023
Mood disorders; Physician–patient relations; Health knowledge; attitudes; practice; Patient compliance; Social support
4.  Early Alliance, Alliance Ruptures, and Symptom Change in a Nonrandomized Trial of Cognitive Therapy for Avoidant and Obsessive–Compulsive Personality Disorders 
Participants were 30 adult outpatients diagnosed with avoidant personality disorder or obsessive–compulsive personality disorder who enrolled in an open trial of cognitive therapy for personality disorders. Treatment consisted of up to 52 weekly sessions. Symptom evaluations were conducted at intake, at Sessions 17 and 34, and at the last session. Alliance variables were patients’ first alliance rating and “rupture-repair” episodes, which are disruptions in the therapeutic relationship that can provide corrective experiences and facilitate change. Stronger early alliances and rupture-repair episodes predicted more improvement in symptoms of personality disorder and depression. This work points to potentially important areas to target in treatment development for these personality disorders.
doi:10.1037/0022-006X.74.2.337
PMCID: PMC3268072  PMID: 16649878
alliance; alliance ruptures; therapeutic alliance; personality disorders; cognitive therapy
5.  Neurosteroids and Self-Reported Pain in Veterans Who Served in the U.S. Military After September 11, 2001 
Pain medicine (Malden, Mass.)  2010;11(10):1469-1476.
Objective
Nearly half of Operation Enduring Freedom / Operation Iraqi Freedom (OEF/OIF) veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABAA receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans.
Design
We determined serum neurosteroid levels by gas chromatography / mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates.
Setting
Durham VA Medical Center.
Results
Allopregnanolone levels were inversely associated with low back pain (p=0.044) and chest pain (p=0.013), and DHEA levels were inversely associated with muscle soreness (p=0.024). DHEAS levels were positively associated with chest pain (p=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (p=0.002).
Conclusions
Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders.
doi:10.1111/j.1526-4637.2010.00927.x
PMCID: PMC2994993  PMID: 20735755
neuroactive steroid; allopregnanolone; pregnenolone; DHEA; nociception; pain; neurosteroid
6.  Change is Not Always Linear: The Study of Nonlinear and Discontinuous Patterns of Change in Psychotherapy 
Clinical psychology review  2007;27(6):715-723.
The study of discontinuities and nonlinear change has been a fruitful endeavor across the sciences, as these shifts can provide a window into the organization of complex systems and the processes that are associated with transition. A common assumption in psychotherapy research has been that change is gradual and linear. The research designs and statistics used to study change often reflect this assumption, but some recent research reveals other patterns of change. We briefly review relevant literature on dynamical systems theory and on life transition and post-traumatic growth to highlight the significance of nonlinear and discontinuous change across areas of psychology. We describe recent applications of these ideas and methods to the study of change in psychotherapy and encourage their use to complement more traditional clinical trial designs.
doi:10.1016/j.cpr.2007.01.008
PMCID: PMC3163164  PMID: 17316941
7.  Allopregnanolone Levels are Reduced in Temporal Cortex in Patients with Alzheimer’s Disease Compared to Cognitively Intact Control Subjects 
Biochimica et biophysica acta  2010;1801(8):951-959.
Background
The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer’s disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers.
Methods
Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects).
Results
Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n= 40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r= −0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04).
Conclusions
Neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. The APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.
doi:10.1016/j.bbalip.2010.05.006
PMCID: PMC2907131  PMID: 20488256
8.  Patient and provider interventions for managing osteoarthritis in primary care: protocols for two randomized controlled trials 
Background
Osteoarthritis (OA) of the hip and knee are among the most common chronic conditions, resulting in substantial pain and functional limitations. Adequate management of OA requires a combination of medical and behavioral strategies. However, some recommended therapies are under-utilized in clinical settings, and the majority of patients with hip and knee OA are overweight and physically inactive. Consequently, interventions at the provider-level and patient-level both have potential for improving outcomes. This manuscript describes two ongoing randomized clinical trials being conducted in two different health care systems, examining patient-based and provider-based interventions for managing hip and knee OA in primary care.
Methods / Design
One study is being conducted within the Department of Veterans Affairs (VA) health care system and will compare a Combined Patient and Provider intervention relative to usual care among n = 300 patients (10 from each of 30 primary care providers). Another study is being conducted within the Duke Primary Care Research Consortium and will compare Patient Only, Provider Only, and Combined (Patient + Provider) interventions relative to usual care among n = 560 patients across 10 clinics. Participants in these studies have clinical and / or radiographic evidence of hip or knee osteoarthritis, are overweight, and do not meet current physical activity guidelines. The 12-month, telephone-based patient intervention focuses on physical activity, weight management, and cognitive behavioral pain management. The provider intervention involves provision of patient-specific recommendations for care (e.g., referral to physical therapy, knee brace, joint injection), based on evidence-based guidelines. Outcomes are collected at baseline, 6-months, and 12-months. The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index (self-reported pain, stiffness, and function), and secondary outcomes are the Short Physical Performance Test Protocol (objective physical function) and the Patient Health Questionnaire-8 (depressive symptoms). Cost effectiveness of the interventions will also be assessed.
Discussion
Results of these two studies will further our understanding of the most effective strategies for improving hip and knee OA outcomes in primary care settings.
Trial registration
NCT01130740 (VA); NCT 01435109 (NIH)
doi:10.1186/1471-2474-13-60
PMCID: PMC3433311  PMID: 22530979
Osteoarthritis; Physical activity; Weight reduction program; Pain management; Intervention study

Results 1-8 (8)