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1.  The Renin-Angiotensin Pathway in PTSD: ACE inhibitor and ARB medications are associated with fewer traumatic stress symptoms 
Objective
PTSD is a debilitating stress-related illness associated with trauma exposure. The peripheral and central mechanisms mediating stress response in PTSD are incompletely understood. Recent data suggest that the renin-angiotensin pathway, essential to cardiovascular regulation, is also involved in mediating stress and anxiety. In this study, the authors examined the relationship between active treatment with blood pressure medication, including angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), and PTSD symptom severity within a highly traumatized civilian medical population.
Method
Cross-sectional, observational data was analyzed from a larger study, recruiting patients from Grady Memorial Hospital's outpatient population from 2006 to November 2010. Multi-variable linear regression models were fit to statistically evaluate the independent association of being prescribed an ACE-I or ARB with PTSD symptoms, using a sub-set of patients for whom medical information was available (n=505). PTSD diagnosis was assessed using the modified PTSD Symptom Scale (PSS) based on DSM-IV criteria with PTSD symptoms based on PSS and Clinician Administered PTSD Scale (CAPS).
Results
A significant association was determined between presence of ACE-I / ARB medication and decreased PTSD symptoms (mean PSS score 11.4 vs 14.9 for individuals prescribed vs not prescribed ACE-I/ARBs, respectively (p = 0.014)). After adjustment for covariates, ACE-I/ARB treatment remained significantly associated with decreased PTSD symptoms (p = 0.044). Notably, other blood pressure medications, including beta-blockers, calcium channel blockers, and diuretics, were not significantly associated with reduced PTSD symptoms.
Conclusions
These data provide the first clinical evidence supporting a role for the reninangiotensin system in the regulation of stress response in patients diagnosed with PTSD. Further studies should examine whether available medications targeting this pathway should be considered for future treatment and potential protection against PTSD symptoms.
doi:10.4088/JCP.11m07316
PMCID: PMC4087173  PMID: 22687631
2.  A 2-Year Prospective Follow-Up Study of the Course of Obsessive-Compulsive Disorder 
The Journal of clinical psychiatry  2010;71(8):1033-1039.
Background
Surprisingly little is known about the long-term course of obsessive-compulsive disorder (OCD). This prospective study presents 2-year course findings, as well as predictors of course, from the Brown Longitudinal Obsessive Compulsive Study, the first comprehensive prospective investigation of the observational course of OCD in a large clinical sample.
Method
The sample included 214 treatment-seeking adults with DSM-IV OCD at intake who identified OCD as the most problematic disorder over their lifetime. Subjects were enrolled from 2001–2004. At annual interviews, data on weekly OCD symptom status were obtained using the Longitudinal Interval Follow-Up Evaluation. Probabilities of full remission and partial remission over the first 2 years of collected data and potential predictors of remission were examined.
Results
The probability of full remission from OCD was 0.06, and the probability of partial remission was 0.24. Of the 48 subjects whose OCD symptoms partially or fully remitted, only 1 relapsed within the first 2 years. Earlier age at onset of OCD, greater severity of symptoms at intake, older age at intake, and being male were associated with a decreased likelihood of remission. Insight, diagnostic comorbidity, and treatment were not found to be associated with the likelihood of achieving full or partial remission.
Conclusions
Though one-quarter of the sample had periods of subclinical OCD symptoms during the prospective period, full remission was rare, consistent with the view of OCD as a chronic and persistent illness. Age at onset, OCD symptom severity, current age, and sex emerged as potent predictors of course.
doi:10.4088/JCP.08m04806blu
PMCID: PMC4083757  PMID: 20797381
3.  Stress and inflammation reduce BDNF expression in first-episode psychosis: a pathway to smaller hippocampal volume 
The Journal of clinical psychiatry  2011;72(12):1677-1684.
Background
Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this study was to investigate potential causes and consequences of reduced BDNF expression in these patients, by examining the association between BDNF levels and measures of stress, inflammation and hippocampal volume in first-episode psychosis.
Methods
BDNF, interleukin (IL)-6, and tumour-necrosis-factor (TNF) alpha mRNA levels were measured in leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, recruited between January 2006 and December 2008. In the same subjects, we measured salivary cortisol levels, and collected information about psychosocial stressors (number of childhood trauma, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured, using brain MRI, in a subsample of 19 patients.
Results
Patients had reduced BDNF (effect size d=1.3, p<0.001) and increased IL-6 (effect size d=1.1, p<0.001) and TNF-alpha (effect size d=1.7, p<0.001) gene expression levels, when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R square=0.23, p=0.009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels, all significantly and independently predicted a smaller left hippocampal volume (adjusted R square=0.71, p<0.001).
Conclusions
Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis, through an effect on BDNF.
doi:10.4088/JCP.10m06745
PMCID: PMC4082665  PMID: 21672499
4.  Less is More in Antidepressant Clinical Trials: A Meta-Analysis of the Effect of Visit Frequency on Treatment Response and Drop-out 
Objective
We investigated how the number of follow-up visits affects response rates and drop-out among patients in antidepressant trials for Major Depressive Disorder (MDD).
Data Sources
Medline, PsycINFO, and PubMed were searched to identify trials contrasting antidepressants to placebo or active comparator in adults with depression. The index terms “depression—drug therapy,” “depressive disorder—drug therapy,” and “antidepressant agents,” in addition to the class and individual generic name of all antidepressants were combined using the ‘or’ operator. Results were limited to 1) English language articles, 2) publication year 1985 or later, 3) age group ≥ 18, and 4) publication types including clinical trials, controlled clinical trials, meta-analysis, multi-center study, randomized controlled trial, or review.
Study Selection
Included articles reported trials of approved antidepressant medications for MDD in outpatients aged 18–65, were 6–12 weeks in duration, and had response rates specified using a standardized measure. Trials were excluded for enrolling inpatients, pregnant women, psychotic subjects, or those with treatment-resistant depression. These criteria allowed 9,189 articles identified in the literature review to be narrowed to 111 reports.
Data extraction
Demographic characteristics, the number of study visits planned in each treatment cell, duration of active treatment, attrition rates, and response rates to medication and placebo were entered into a database.
Results
In a multilevel meta-analysis, active medication vs. placebo (OR 1.96, p < 0.001), active comparator vs. placebo-controlled study design (OR 1.82, p < 0.001), and longer vs. shorter duration (OR 1.87, p < 0.001) were associated with significantly increased odds of treatment response. After controlling for these variables, the number of study visits did not significantly influence response rates (OR 0.97, p = 0.877). The odds of drop-out were significantly decreased for active comparator vs. placebo-controlled trials (OR 0.67, p = 0.002) and longer vs. shorter duration trials (OR 0.54, p = 0.035), while increasing numbers of study visits significantly increased the odds of participant drop-out (OR 2.77, p < 0.001).
Conclusion
Visit schedules that are much more frequent than are commonly practiced in the community treatment of depression may increase the expense of clinical trials and make them less generalizable to standard clinical treatment.
doi:10.4088/JCP.12r08267
PMCID: PMC3898620  PMID: 23945448
5.  Omega-3 Polyunsaturated Fatty Acid Status in Major Depression with Comorbid Anxiety Disorders 
Objective
Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depression, less is known about PUFA status and anxiety disorders.
Method
Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n=18) and without (n=41) comorbid anxiety disorders, and healthy volunteers (n=62) were recruited from October 2006 to May 2010 at the New York State Psychiatric Institute. Depression and anxiety severity were assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (20:5n-3, EPA), docosahexaenoic acid (22:6n-3, DHA), and the ratio of arachidonic acid (22:4n-6, AA) to EPA (AA:EPA) were quantified. This secondary analysis employed ANOVA with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA).
Results
Plasma levels of logDHA (F=4.92, df=2,118, p=0.009), logEPA (F=6.44, df=2,118, p=0.002), and logAA:EPA (F=3.81, df=2,118, p=0.025) differed across groups. MDD participants had lower logDHA (t=2.324, df=118, p=0.022) and logEPA (t=3.175, df=118, p=0.002) and higher logAA:EPA (t=–2.099, df=118, p=0.038) compared with healthy volunteers. Lower logDHA (t=2.692, df=118, p=0.008), logEPA (t=2.524, df=118, p=0.013), and higher logAA:EPA (t=–2.322, df=118, p=0.022) distinguished anxious from non-anxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (rp=–0.22, p=0.015) and logEPA (rp=–0.25, p=0.005) and positively with logAA:EPA (rp=0.18, p=0.043).
Conclusions
The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety.
doi:10.4088/JCP.12m07970
PMCID: PMC3905735  PMID: 23945451
Anxiety Disorders; Omega-3; Polyunsaturated fatty acids; Major Depressive Disorder
6.  Alzheimer’s Disease: Implications of the Updated Diagnostic and Research Criteria 
The Journal of clinical psychiatry  2011;72(9):1190-1196.
doi:10.4088/JCP.10087co1c
PMCID: PMC4068242  PMID: 21951985
8.  Suicide Risk Assessment Received Prior to Suicide Death by Veterans Health Administration Patients with a History of Depression 
Objective
To examine the quality of suicide risk assessment provided to veterans with a history of depression who died by suicide between 1999-2004.
Methods
Case-control study of suicide risk assessment information recorded in 488 medical charts of veterans previously diagnosed with Major Depression, Depression NOS, Dysthymia, or other, less common depression codes. Patients dying of suicide or comparison patients (n=244 pairs) were matched for age, sex, entry-year, and region.
Results
74% of patients with a history of depression received a documented assessment of suicidal ideation within the past year, and 59% received more than one assessment. However, 70% of patients of those who died of suicide did not have a documented assessment for suicidal ideation at their final VHA visit, even if that visit occurred within 0-7 days prior to suicide death. Most patients dying by suicide denied suicidal ideation when assessed (85%, 95% CI 75%-92%), even just 0-7 days prior to suicide death (73%, 95% CI 39%-94%). Suicidal ideation was assessed more frequently during outpatient final visits with mental health providers (60%) than during final visits with primary care (13%) or other non-mental health providers (10%) (p<0.0001).
Conclusions
Most VHA patients with a history of depression received some suicide risk assessment within the past year, but suicide risk assessments were infrequently administered at the final visit of patients who eventually died by suicide. Among patients who had assessments, denial of suicidal ideation appeared to be of limited value. Practice changes are needed to improve suicide risk assessment among patients with histories of depression, including the development of assessment and prevention strategies that are less dependent on the presence or disclosure of suicidal ideation at scheduled medical visits.
doi:10.4088/JCP.12m07853
PMCID: PMC4055158  PMID: 23561227
9.  Effect of Second Generation Antipsychotics on Caregiver Burden in Alzheimer Disease 
Context
Alzheimer disease (AD) imposes a severe burden upon patients and their caregivers. Severity of psychiatric symptoms and behavioral disturbances are important determinants of caregivers’ experience of burden. These symptoms may be improved with atypical antipsychotic treatment.
Objective
In this study we use data from the CATIE-AD trial to evaluate the effect of atypical antipsychotics as compared to placebo on the experiences of caregivers of outpatients with Alzheimer disease.
Design
We compared the effect of atypical antipsychotic drugs (olanzapine, risperidone or quetiapine) considered together as a group, to placebo, on experiences of caregivers of AD outpatients. We also evaluated whether improvement in patients’ psychiatric and behavioral symptoms mediated the relationship between drug treatment and caregiver burden.
Setting
CATIE-AD included outpatients in usual care settings, and assessed treatment effectiveness over a nine-month period.
Participants
Data from CATIE-AD participants who had at least one post-baseline outcome assessment, and from their caregivers, were examined in an intention-to-treat analysis (ITT) (N=361), and then in a phase 1 only analysis including only observations while on the initially randomized drug (N=153).
Measures
The Burden Interview, Beck Depression Inventory, and the NPI Caregiver Distress Scale were used to evaluate caregiver burden.
Results
In both ITT and phase 1-only analyses, caregivers of patients treated with second generation antipsychotics (SGAs) scored significantly lower than those on placebo on both the Burden Interview (p = 0.009) and the NPI Caregiver Distress Scale’s scores (p = 0.0209). These differences appeared to have been mediated by lower levels of agitation, hostility, and psychotic distortions.
Conclusion
In AD patients with symptoms of psychosis, agitation or aggressive behavior, medications can have a small but significant impact on caregiver burden.
doi:10.4088/JCP.10m06574
PMCID: PMC4040971  PMID: 21939611
Caregivers Burden; Alzheimer Disease; Antipsychotic
10.  A Meta-Analysis of the Risk of Acute Extrapyramidal Symptoms with Intramuscular Antipsychotics for the Treatment of Agitation 
The Journal of clinical psychiatry  2008;69(12):1869-1879.
OBJECTIVE
We examined the evidence for a decreased risk of extrapyramidal symptoms (EPS) with intramuscular second-generation antipsychotics (SGAs) versus intramuscular haloperidol alone or in combination with an anticholinergic agent.
DATA SOURCES
We searched MEDLINE, EMBASE, and the Cochrane Registry for studies published in English of intramuscular SGAs and intramuscular haloperidol alone or in combination with an anticholinergic agent. Initially, we included only randomized controlled trials (RCTs). To obtain more data comparing SGAs to the combination of haloperidol and an anticholinergic, we conducted a second analysis including studies of any methodology.
STUDY SELECTION
Seven RCTs that compared SGAs to haloperidol alone were identified. However, we found only one RCT of haloperidol plus an anticholinergic. In the second analysis, we identified 18 studies, including four using haloperidol combined with promethazine (an antihistamine with anticholinergic properties).
DATA EXTRACTION
The primary outcome measure was acute dystonia; secondary outcomes included akathisia, parkinsonism, or additional anticholinergic medication. For RCTs, risk ratios (RR) and 95% confidence intervals (CI) were calculated for each outcome. When all studies were included in the second analysis, we calculated the risk of acute dystonia.
DATA SYNTHESIS
Among RCTs (N=2032), SGAs were associated with a significantly lower risk of acute dystonia (RR 0.19, CI 0.10-0.39), akathisia (RR 0.25, CI 0.14-0.45), and anticholinergic use (RR 0.19, CI 0.09-0.43) compared with haloperidol alone. When all trials were considered (N=3425), rates of acute dystonia were higher for haloperidol alone (4.7%) than SGAs (0.6%) or haloperidol plus promethazine (0%).
CONCLUSIONS
Intramuscular SGAs have a significantly lower risk of acute EPS compared to haloperidol alone. However, intramuscular haloperidol plus promethazine has a risk of acute dystonia comparable to intramuscular SGAs. The decision to use SGAs should consider other factors in addition to the reduction of EPS, which can be prevented by the use of an anticholinergic agent.
PMCID: PMC4041731  PMID: 19192477
antipsychotic drugs; extrapyramidal symptoms; dystonia; agitation; intramuscular
11.  Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers 
Objective
The authors studied the lifetime prevalence of DSM-IV-TR psychiatric disorders in a population of adults with the fragile X premutation.
Methods
Structured Clinical Interview for DSM-IV (SCID) were conducted on 85 individuals with the fragile X premutation, 47 with the fragile X-associated tremor/ataxia syndrome (FXTAS; 33 male, 14 female, mean age 66) and 38 without FXTAS (16 male, 22 female, mean age 52). Lifetime prevalence for mood and anxiety disorders among carriers with and without FXTAS was compared to available age-specific population estimates from the National Comorbidity Survey Replication (NCS-R).
Results
Among subjects with FXTAS, 30 cases (65%) met lifetime DSM-IV-TR criteria for mood disorder; 24 cases (52%) met lifetime DSM-IV-TR criteria for anxiety disorder. Among the non-FXTAS subjects, there were 15 cases (42%) of lifetime mood disorder and 18 cases (47%) of lifetime anxiety disorder. When compared to age-specific NCS-R data, the lifetime prevalence of any mood disorder, major depressive disorder, any anxiety disorder, panic disorder, specific phobia, and PTSD were significantly higher in subjects with FXTAS. The lifetime rates of social phobia in individuals with the premutation without FXTAS were significantly higher than NCS-R data.
Conclusions
This sample of carriers of the fragile X premutation had a notably high lifetime risk of mood and anxiety disorders. Mood and anxiety disorders may be part of the clinical phenotype of the fragile X premutation conditions, especially in carriers with FXTAS. Clinicians encountering these patients are advised to consider FXTAS as a neuropsychiatric syndrome as well as a neurological disorder.
doi:10.4088/JCP.09m05407blu
PMCID: PMC4038118  PMID: 20816038
Fragile X syndrome; fragile X-associated tremor/ataxia syndrome; FMR1 gene; (FXTAS); mood disorders; anxiety disorders
12.  Prevalence of Attenuated Psychotic Symptoms and their Relationship with DSM-IV Diagnoses in a General Psychiatric Outpatient Clinic 
Objective
Attenuated psychosis syndrome (APS) is being proposed for DSM-5 for those impaired by subthreshold psychotic symptoms that are not better accounted for by another diagnosis and not meeting criteria for a psychotic disorder. The rationale is to identify patients who are at high risk for transition to a psychotic disorder in the near future. However, the potential impact of using this new diagnosis in routine clinical practice settings has not been carefully examined.
Method
We investigated the prevalence rate of endorsing attenuated psychotic experiences (PEs) in a treatment-seeking psychiatric outpatient sample (n = 1,257) recruited from June 1997 to June 2002 to identify patients who could potentially meet criteria for APS. Patients completed a self-report measure of psychiatric symptoms and afterward were administered structured clinical interviews.
Results
After excluding those with lifetime DSM-IV psychotic disorders, PEs remained highly prevalent in the sample (28% reported at least one current PE) and rates were similar across all major diagnostic categories. Only 1 patient (0.08%) reported PEs but did not meet criteria for another current DSM disorder; however, this individual endorsed other nonpsychotic symptoms of greater severity. PE endorsement was positively correlated with nearly all other nonpsychotic symptom domains and multivariate analysis showed that general clinical severity predicted endorsement of PEs (ps < .001).
Conclusion
We could not identify any patients likely meeting criteria for APS alone in our sample. PEs appear to be common in outpatients and represent nonspecific indicators of psychopathology. Diagnosing APS in the community could result in high rates of false positives or high rates of APS “comorbidity” with other nonpsychotic disorders, leading to the increased use of antipsychotic medications without clear need. Therefore, the clinical utility of adding APS to the diagnostic system remains highly questionable.
doi:10.4088/JCP.12m07788
PMCID: PMC4036523  PMID: 23146173
psychosis; diagnosis; attenuated psychosis syndrome; DSM-5; routine clinical practice
13.  Clinical and Cognitive Correlates of Suicide Attempts in Bipolar Disorder: Is Suicide Predictable? 
The Journal of clinical psychiatry  2011;72(8):1027-1033.
Objective
We conducted a retrospective investigation of potential clinical, demographic, and neuropsychological risk factors for suicide attempts in patients diagnosed with bipolar disorder.
Method
Participants included 67 adult inpatients and outpatients aged 18–60 years meeting DSM-IV criteria for bipolar disorder (bipolar I and II disorders, bipolar disorder not otherwise specified). We assessed demographic factors, mood symptoms, psychosis, trauma history, trait impulsivity, trait aggression, and reasons for living. The primary outcome measures were the Barratt Impulsiveness Scale-version II, Aggression Questionnaire, and 10 cognitive outcome variables. The cognitive outcome variables assessed cognitive performance across several domains, including processing speed, attention, verbal learning, and executive function. Another aspect of cognitive function, decision making, was assessed using the Iowa Gambling Task. The study was conducted from July 2007–July 2009.
Results
We found that nonattempters reported significantly higher trait impulsivity scores on the Barratt Impulsiveness Scale compared to attempters (t57 = 2.2, P = .03) and that, among attempters, lower trait impulsivity score was associated with higher scores of lethality of prior attempts (r25 = −0.53, P = .01). Analyses revealed no other group differences on demographic, clinical, or neurocognitive variables when comparing attempters versus nonattempters. Regression models failed to identify any significant predictors of past suicide attempt.
Conclusions
The largely negative results of our study are particularly important in highlighting the clinical dilemma faced by many clinicians when trying to predict which patients will make serious suicide attempts and which patients are at a lower risk for acting on suicidal thoughts. A limitation of our work is that we examined stable trait measures of impulsivity among a euthymic sample rather than mood state or the impact of mood state on traits. Overall, we conclude that suicidal behavior is extremely difficult to predict, even when comprehensive clinical and neurocognitive information is available.
doi:10.4088/JCP.10m06410
PMCID: PMC4035109  PMID: 21813075
15.  Bupropion for Overweight Women with Binge Eating Disorder: Randomized Double-blind Placebo-controlled Trial 
Background
Binge eating disorder (BED) is defined by recurrent binge eating (eating unusually large quantities of food during which a subjective loss of control is experienced), marked distress about the binge eating, and the absence of inappropriate weight compensatory behaviors. BED is strongly associated with excess weight and many available psychological and pharmacological approaches fail to produce much weight loss. The objective of this study was to perform a randomized placebo-controlled trial to evaluate the short-term efficacy of bupropion for the treatment of BED in overweight and obese women.
Methods
Sixty-one overweight and obese (Mean BMI=35.8) women with BED were randomly assigned to receive bupropion (300 mg/d) or placebo for 8 weeks. Participants were enrolled from November 2006 to December 2010. No dietary or lifestyle intervention was given. Primary outcome measures were binge-eating frequency and percent BMI loss. Secondary outcome measures were dimensional measures of eating disorder psychopathology, food craving, and depression levels.
Results
Eighty-nine percent of randomized participants completed the trial without differential dropout between bupropion and placebo. Mixed effects analyses revealed significant time effects for all outcomes but that bupropion and placebo did not differ significantly on any outcome measure except for weight loss. Participants taking bupropion lost significantly more weight (1.8% BMI loss versus 0.6% BMI loss; F=10.57, p=002).
Conclusions
Bupropion was well tolerated and produced significantly greater – albeit quite modest – short-term weight loss in overweight and obese women with BED. Bupropion did not improve binge eating, food craving, or associated eating disorder features or depression relative to placebo. Our findings do not support bupropion as a stand-alone treatment for BED. The preliminary findings regarding short-term weight losses suggest the need for larger and longer-term trials to evaluate the potential utility of bupropion for enhancing outcomes of psychological interventions with demonstrated effectiveness for BED but which fail to produce weight loss.
doi:10.4088/JCP.12m08071
PMCID: PMC4021866  PMID: 23656848
bupropion; binge eating disorder; obesity; weight loss; food craving; pharmacotherapy
16.  Impact of Physiologic Estrogen Replacement on Anxiety Symptoms, Body Shape Perception and Eating Attitudes in Adolescent Girls with Anorexia Nervosa: Data from a Randomized Controlled Trial 
The Journal of clinical psychiatry  2013;74(8):e765-e771.
Objectives
Anorexia nervosa (AN) is characterized by low weight, aberrant eating attitudes, body image distortion and hypogonadism. Anxiety is a common co-morbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in AN. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes, without affecting body image in AN.
Methods
Girls with AN (DSM-IV) 13–18 yo were randomized to transdermal estradiol (100-mcg twice weekly) with cyclic progesterone (AN-E+) or placebo patches and pills (AN-E−) for 18-months, between 2002 and 2010. The Spielberger’s State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory II (EDI II), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these at baseline (38 AN-E+ and 34 AN-E−), and 37 at 18-months (20 AN-E+ and 17 AN-E−). The primary outcome measure was the change in these scores over 18-months.
Results
Estrogen replacement caused a decrease in STAIC-trait scores (−3.05±1.22 vs. 2.07±1.73, p=0.02), without impacting STAI-state scores (−1.11±2.17 vs. 0.20±1.42, p=0.64). There was no effect of estrogen replacement on EDI II or BSQ-34 scores. BMI changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (p=0.03). There was an inverse association between serum estradiol changes and changes in STAIC-trait scores (r=−0.66, p=0.001).
Conclusions
Estrogen replacement improved trait anxiety (the tendency to experience anxiety), but did not impact eating attitudes or body shape perception.
doi:10.4088/JCP.13m08365
PMCID: PMC4017248  PMID: 24021517
Estrogen; anxiety; eating behavior; body shape; anorexia nervosa; adolescents
17.  Current Status of Ketamine and Related Compounds for Depression 
doi:10.4088/JCP.13ac08382
PMCID: PMC3785314  PMID: 23759454
ketamine; NMDA; antidepressant; depression; bipolar; glutamate; novel
18.  A Case-Controlled Study of Successful Aging in Older Adults with HIV 
The Journal of clinical psychiatry  2013;74(5):e417-e423.
OBJECTIVES
There is a growing public health interest in the aging HIV-infected (HIV+) population, although there is a dearth of research on successful aging with HIV. This study aimed to understand the risk and protective factors associated with self-rated successful aging (SRSA) with HIV.
DESIGN
Cross-sectional, case-controlled.
SETTING
HIV Neurobehavioral Research Program and the Stein Institute for Research on Aging at University of California, San Diego.
PARTICIPANTS
Eighty-three community-dwelling HIV+ and 83 demographically matched HIV-uninfected (HIV−) individuals, enrolled between 12/1/11 and 5/10/12, mean age of 59 years, primarily Caucasian males, 69% with AIDS, who had been living with an HIV diagnosis for 16 years. Diagnostic criteria for HIV/AIDS was obtained through a blood draw.
MEASUREMENTS
Participants provided ratings of SRSA as part of a comprehensive survey which included measures of physical and emotional functioning and positive psychological traits. Relationships between how the different variables related to SRSA were explored.
RESULTS
While SRSA was lower in the HIV+ individuals than their HIV− counterparts, 66% of adults with HIV reported scores of 5 or higher on a 10-point scale of SRSA. Despite worse physical and mental functioning and greater psychosocial stress among the HIV+ participants, the two groups had comparable levels of optimism, personal mastery, and social support. SRSA in HIV+ individuals was associated with better physical and emotional functioning and positive psychological factors, but not HIV disease status or negative life events.
CONCLUSION
Successful psychosocial aging is possible in older HIV+ individuals. Positive psychological traits such as resilience, optimism, and sense of personal mastery have stronger relationship with SRSA than duration or severity of HIV disease. Research on interventions to enhance these positive traits in HIV+ adults is warranted.
doi:10.4088/JCP.12m08100
PMCID: PMC3683870  PMID: 23759460
HIV/AIDS; successful aging; physical function; emotional function; positive psychological factors; depression
19.  Postprandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa 
The Journal of clinical psychiatry  2013;74(5):e451-e457.
Objective
Anorexia nervosa, a psychiatric disorder characterized by self-induced starvation, is associated with endocrine dysfunction and comorbid anxiety and depression. Animal data suggest that oxytocin may have anxiolytic and antidepressant effects. We have reported increased postprandial oxytocin levels in women with active anorexia nervosa (AN), and decreased levels in weight-recovered women with anorexia nervosa (ANWR) compared to healthy controls (HC). A meal may represent a significant source of stress in patients with disordered eating. We therefore investigated the association between post-prandial oxytocin secretion and symptoms of anxiety and depression in anorexia nervosa.
Method
We performed a cross-sectional study of 35 women (13 AN, 9 ANWR and 13 HC). Serum oxytocin and cortisol and plasma leptin levels were measured fasting and 30, 60, and 120min after a standardized mixed meal. The area under the curve (AUC), and for oxytocin, postprandial nadir and peak levels were determined. Anxiety and depressive symptoms were assessed using the Spielberger State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory II (BDI-II).
Results
In women with anorexia nervosa, oxytocin AUC and post-prandial nadir and peak levels were positively associated with STAI scores. Oxytocin AUC and nadir levels were positively associated with BDI-II scores. After controlling for cortisol AUC, most relationships remained significant. After controlling for leptin AUC, all of the relationships remained significant. Oxytocin secretion explained up to 51% of the variance in STAI trait and 24% of BDI-II scores.
Conclusions
Abnormal post-prandial oxytocin secretion in women with anorexia nervosa is associated with increased symptoms of anxiety and depression. This may represent an adaptive response of oxytocin secretion to food-related symptoms of anxiety and depression.
doi:10.4088/JCP.12m08154
PMCID: PMC3731039  PMID: 23759466
Anorexia nervosa; oxytocin; anxiety; depression; cortisol; leptin
20.  Antidepressant Augmentation Using the NMDA-Antagonist Memantine: A Randomized, Double-Blind, Placebo-Controlled Trial 
The Journal of clinical psychiatry  2013;74(10):966-973.
Objective
Intravenous NMDA antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial (NCT00344682) of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder.
Method
31 participants with partial or nonresponse to their current antidepressant were randomized (from 2006–2011) to add memantine (flexible dose 5–20 mg/day, with all memantine group participants reaching the dose of 20 mg/day) (n= 15) or placebo (n= 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects.
Results
Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (β=0.133, favoring placebo, p=0.74) or at study completion (week 8 MADRS score change: −7.13 +/−6.61 (memantine); −7.25 +/−11.14 (placebo), p=0.97). A minimal-to-small effect size (comparing change to baseline variability) was observed (d=0.19), favoring placebo. Similarly, no substantial effect sizes favoring memantine, nor statistically significant between-group differences, were observed on secondary efficacy or safety outcomes.
Conclusions
This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment against major depressive disorder.
doi:10.4088/JCP.12m08252
PMCID: PMC4000742  PMID: 24229746
21.  Risk-Taking Propensity as a Predictor of Induction onto Naltrexone Treatment for Opioid Dependence 
The Journal of clinical psychiatry  2012;73(8):e1056-e1061.
Objective
Heroin addiction is a chronic relapsing disorder that has devastating social, medical, and economic consequences. Naltrexone is an antagonist that blocks opioid effects and could be an effective medication for the treatment of opioid dependence. However, its clinical utility has been limited partly because of poor adherence and acceptability. Given the importance of compliance to naltrexone treatment for opioid dependence, the goal of the current study was to examine predictors involved in successful induction onto naltrexone treatment.
Method
Parametric and nonparametric statistical tests were performed on data from a sample of 64 individuals entering treatment who met DSM-IV criteria for opioid dependence. The relationship between naltrexone induction (i.e., inducted- vs. not-inducted onto naltrexone) and risk-taking propensity, as indexed by riskiness on the Balloon Analogue Risk Task (BART) was examined. Participants were recruited from local detoxification programs, inpatient drug treatment, and other Baltimore programs that provided services to opioid dependent adults (e.g., Baltimore Needle Exchange Program) during the period from August 2007 to September 2008.
Results
Positive association between risk-taking propensity and odds of naltrexone induction. Specifically, each five point increase in the total BART score was associated with a 25% decrease in odds of naltrexone induction (OR=0.76, 95% CI: 0.58–0.99, p = .041). This association remained statistically significant even after adjusting for potential confounds, including injection drug use and cocaine positive urine results (p = .05). After adjusting for the covariates, each five point increase in BART score was associated with 28% decrease in the odds of achieving the maintenance dose (AOR=0.73, 95% CI: 0.54–0.99, p = .046).
Conclusions
Risk taking propensity was predictive of induction onto naltrexone treatment, above and beyond injection drug use and cocaine-positive urine samples.
doi:10.4088/JCP.09m05807
PMCID: PMC3985274  PMID: 22967782
Risk taking propensity; naltrexone; opioid dependence; substance abuse treatment
22.  The CAD-MDD: A Computerized Adaptive Diagnostic Screening Tool for Depression 
Objective
To develop a computerized adaptive diagnostic (CAD) screening tool for depression that decreases patient and clinician burden and increases sensitivity and specificity for clinician-based DSM-IV diagnosis of major depressive disorder (MDD).
Method
656 individuals with and without minor and major depression were recruited from a psychiatric clinic, community mental health center, and through public announcements (controls without depression). The item bank consists of 88 depression scale items drawn from 73 depression measures. The focus of this study was the development of the CAD-MDD diagnostic screening tool based on a decision-theoretic approach (random forests and decision trees). Sensitivity and specificity for predicting clinician-based SCID DSM-IV diagnoses of MDD were the primary outcomes. Diagnostic screening accuracy was then compared to the PHQ-9.
Results
An average of 4 items per participant was required (maximum of 6 items). Overall sensitivity and specificity were 0.95 and 0.87 respectively. For the PHQ-9, sensitivity was 0.70 and specificity was 0.91.
Conclusion
High sensitivity and reasonable specificity for a clinician-based DSM-IV diagnosis of depression can be obtained using an average of 4 adaptively administered self-report items in less than one minute. Relative to the currently used PHQ-9, the CAD-MDD dramatically increased sensitivity while maintaining similar specificity. As such, the CAD-MDD will identify more true positives (lower false negative rate) than the PHQ-9 using half the number of items. Inexpensive (relative to clinical assessment), efficient and accurate screening of depression in primary care settings, psychiatric epidemiology, molecular genetics, and global health are all direct applications of the current system.
doi:10.4088/JCP.12m08338
PMCID: PMC3977175  PMID: 23945443
23.  Six-Month Follow-Up of a Randomized Controlled Trial Augmenting Serotonin Reuptake Inhibitor Treatment With Exposure and Ritual Prevention for Obsessive-Compulsive Disorder 
Objective
This article describes the long-term effects of augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention or stress management training in patients with DSM-IV obsessive-compulsive disorder (OCD).
Method
Between November 2000 and November 2006, 111 OCD patients from 2 academic outpatient centers with partial SRI response were randomized to the addition of exposure and ritual prevention or stress management training, delivered twice weekly for 8 weeks (acute phase); 108 began treatment. Responders (38 of 52 in the exposure and ritual prevention condition, 11 of 52 in the stress management training condition) entered a 24-week maintenance phase. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was the primary outcome measure.
Results
After 24 weeks, patients randomized to and receiving exposure and ritual prevention versus stress management training had significantly better outcomes (mean YBOCS scores of 14.69 and 21.37, respectively; t = 2.88, P = .005), higher response rates (decrease in YBOCS scores ≥ 25%: 40.7% vs 9.3%, Fisher exact test P < .001), and higher rates of excellent response (YBOCS score ≤ 12: 24.1% vs 5.6%, Fisher exact test P = .01). During the maintenance phase, the slope of change in YBOCS scores was not significant in either condition (all P values ≥ .55), with no difference between exposure and ritual prevention and stress management training (P > .74). Better outcome was associated with baseline variables: lower YBOCS scores, higher quality of life, fewer comorbid Axis I diagnoses, and male sex.
Conclusions
Augmenting SRIs with exposure and ritual prevention versus stress management training leads to better outcome after acute treatment and 24 weeks later. Maintenance outcome, however, was primarily a function of OCD severity at entrance. Greater improvement during the acute phase influences how well patients maintain their gains, regardless of treatment condition.
doi:10.4088/JCP.12m08017
PMCID: PMC3977336  PMID: 23759449
24.  Treatment Response, Symptom Remission and Wellness in Obsessive-Compulsive Disorder 
Objective
Obsessive-compulsive disorder (OCD) is defined both by intrusive, unwanted thoughts, images or impulses and by repetitive behavioral or mental acts that are often performed to try to alleviate anxiety. The ultimate goal of treatment for OCD is to reduce the symptoms, as well as help patients achieve “wellness”, however currently there are no widely accepted, empirically supported criteria for determining wellness in OCD.
Method
Building on previous research, the current study pooled data from four OCD treatment trials (N = 288) that took place between 1990–2011to examine the Yale-Brown Obsessive Compulsive Disorder Scale (Y-BOCS) score that most reliably identified patients who responded to treatment, those who achieved symptom remission and those who achieved wellness.
Results
Signal detection analyses showed that a pre- to post-treatment reduction of ≥ 35% on the Y-BOCS was most predictive of treatment response, as defined by the Clinical Global Impressions (CGI-Improvement). A post-treatment Y-BOCS score of ≤ 14 was the best predictor of symptom remission, where a score of ≤ 12 was the best predictor of wellness, as defined by symptom remission defined by the CGI-Severity, good quality of life as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (QLES-Q) and a high-level of adaptive function as assessed by the Social Adjustment Scale (SAS-SR).
Conclusions
Empirically supported criteria for defining wellness in OCD can facilitate comparisons across treatment outcome studies and inform clinical treatment planning.
doi:10.4088/JCP.12m07789
PMCID: PMC3959901  PMID: 23945445
obsessive-compulsive disorder; treatment response; symptom remission; wellness; signal detection

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