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2.  The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers 
There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials.
We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains.
This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05).
We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches.
PMCID: PMC4331113  PMID: 24816373
composite cognitive score; API; Alzheimer’s Prevention Initiative; E280A; PSEN1; presenilin1; sample size; preclinical; cognitively unimpaired; autosomal dominant; ADAD
3.  Modeling Trajectory of Depressive Symptoms Among Psychiatric Inpatients: A Latent Growth Curve Approach 
Changes in the parameters of inpatient psychiatric care have inspired a sizable literature exploring correlates of prolonged intervention as well as symptom change over varying lengths of hospitalization. However, existing data offer limited insight regarding the nature of symptom change over time. Objectives of this longitudinal research were to (a) model the trajectory of depressive symptoms within an inpatient psychiatric sample, (b) identify characteristics associated with unique patterns of change, and (c) evaluate the magnitude of expected gains using objective clinical benchmarks.
Participants included psychiatric inpatients treated between April 2008 and December 2010. Latent growth curve modeling was used to determine the trajectory of Beck Depression Inventory II depressive symptoms in response to treatment. Age, gender, trauma history, prior hospitalization, and DSM-IV diagnoses were examined as potential moderators of recovery.
Results indicate a nonlinear model of recovery, with symptom reductions greatest following admission and slowing gradually over time. Female gender, probable trauma exposure, prior psychiatric hospitalization, and primary depressive diagnosis were associated with more severe trajectories. Diagnosis of alcohol/substance use, by contrast, was associated with more moderate trajectories. Objective benchmarks occurred relatively consistently across patient groups with clinically significant change occurring between 2–4 weeks post-admission.
The nonlinear trajectory of recovery observed in these data provides insight regarding the dynamics of inpatient recovery. Across all patient groups, symptom reduction was most dramatic in the initial week of hospitalization. However, notable improvement continued for several weeks post-admission. Results suggest timelines for adequate inpatient care are largely contingent on program-specific goals.
PMCID: PMC4313384  PMID: 23759452
inpatient treatment; psychiatric hospitalization; depression; symptom trajectory; latent growth curve modeling
4.  SSRI versus bupropion effects on symptom clusters in suicidal depression: post-hoc analysis of a randomized clinical trial 
Identifying the depression symptoms most closely associated with suicidal thoughts and which medications provide the fastest relief may help suicide prevention.
Post hoc analysis of data from a randomized, double-blind, eight-week clinical trial of the serotonin reuptake inhibitor paroxetine (N=36) versus the norepinephrine-dopamine reuptake inhibitor bupropion (N=38) in patients with DSM-IV major depressive disorder and past suicide attempt or current suicidal thoughts. Treatment effects on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory symptom clusters were compared. We hypothesized a superior effect of paroxetine on non-suicide, affective/cognitive depression symptom clusters that our prior work found to be associated with suicidal thoughts and attempts. Data were collected from February 2005 to January 2010.
There was a treatment main effect on HDRS Psychic Depression (depressed mood, guilt, retardation, helpless, hopeless, worthless) (estimate = −2.2, 95% CI = −3.2 to −1.1, t = −4.01, df = 67.16, p < 0.001), one of the clusters most strongly correlated to suicidal ideation. The net drug effect was 2.2 points lower average Psychic Depression scores after one week of paroxetine, compared to bupropion, and was statistically significant until Week 4. Results for other depression scale factors were non-significant (p > 0.05).
The results require replication, but suggest a pathway by which SSRI treatment may exert a stronger effect compared with NDRI treatment on reduction of suicidal thoughts during initial weeks of pharmacotherapy in these higher risk patients.
PMCID: PMC4313534  PMID: 24107760
Suicide; depression; symptom cluster; antidepressant; clinical trial
5.  Depressed parents' attachment: effects on offspring suicidal behavior in a longitudinal, family study 
To investigate relationships of depressed parents' attachment style to offspring suicidal behavior.
244 parents diagnosed with a DSM-IV depressive episode completed the Adult Attachment Questionnaire at study entry. Baseline and yearly follow-up interviews of their 488 offspring tracked suicidal behavior and psychopathology. Survival analysis and marginal regression models with correlated errors for siblings investigated the relationship between parent insecure attachment traits and offspring characteristics. Data analyzed were collected 1992–2008 during a longitudinal family study completed January 31, 2014.
Parent avoidant attachment predicted offspring suicide attempts at a trend level (p=0.083). Parent anxious attachment did not predict offspring attempts (p=0.961). In secondary analyses, anxious attachment in parents was associated with offspring impulsivity (p=0.034), and in offspring suicide attempters, was associated with greater intent (p=0.045) and lethality of attempts (p=0.003). Avoidant attachment in parents was associated with offspring impulsivity (p=0.025) and major depressive disorder (p=0.012). Parent avoidant attachment predicted a greater number of suicide attempts (p=0.048) and greater intent in offspring attempters (p=0.003). Results were comparable after adjusting for parent diagnosis of borderline personality disorder.
Insecure avoidant, but not anxious, attachment in depressed parents may predict offspring suicide attempt. Insecure parent attachment traits were associated with impulsivity and major depressive disorder in all offspring, and with more severe suicidal behavior in offspring attempters. Insecure parental attachment merits further study as a potential target to reduce risk of offspring psychopathology and more severe suicidal behavior.
PMCID: PMC4311521  PMID: 25098943
Attachment; Suicide attempt; Family study; Impulsivity; Depression
6.  Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression 
The Journal of clinical psychiatry  2014;75(5):e417-e423.
The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically-heterogeneous populations.
Treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I/II depression currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute post-infusion time point (N=108), at Day 1 (N=82), and at Day 7 (N=71). Univariate Pearson correlations were performed for each variable with change-from-baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (p<0.05, two-tailed).
Higher body mass index (BMI) correlated with greater HDRS improvement at 230 minutes and at Day 1 (standardized β=−0.30, p=0.004), but not at Day 7 (standardized β=−0.18, p=0.10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at Day 1 (standardized β=−0.37, p=0.001) and Day 7 (standardized β=−0.41, p<0.001). No prior history of suicide attempt(s) was associated with greater improvement only at Day 7 (standardized β=0.28, p=0.01). The overall statistical model explained 13, 23, and 36 percent of HDRS percent change variance at 230 minutes, Day 1, and Day 7, respectively.
Despite its post-hoc nature, the study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.
PMCID: PMC4310499  PMID: 24922494
clinical predictors; moderators; mediators; major depression; ketamine; NMDA receptor antagonist
7.  Memantine for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): A Randomized, Double-Blind, Placebo-Controlled Trial 
Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.
A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.
Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007).
This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.
PMCID: PMC4296896  PMID: 24345444
8.  [No title available] 
PMCID: PMC4293026  PMID: 25188543
9.  Clinical Correlates of Patients With Rapid-Cycling Bipolar Disorder and a Recent History of Substance Use Disorder: A Subtype Comparison From Baseline Data of 2 Randomized, Placebo-Controlled Trials 
The Journal of clinical psychiatry  2008;69(7):1057-1063.
To compare clinical variables in patients with rapid-cycling bipolar I or II disorder and a recent history of substance use disorder (SUD).
Cross-sectional data from 2 studies of patients with rapid-cycling bipolar I disorder or rapid-cycling bipolar II disorder and a recent history of SUD were used to retrospectively assess the differences in clinical variables between the subtypes. The studies were conducted from November 1997 to February 2007 at University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Extensive clinical interview and the Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid-cycling bipolar disorder, SUDs, and other Axis I disorders and to collect clinical variables. The Addiction Severity Index (ASI), Global Assessment Scale (GAS), and the Medical Outcomes Study 36-ltem Short-Form Health Survey were used to measure the severity of impairment at the initial assessment. One-way analysis of variance or χ2 was used for significance tests. A Bonferroni adjustment was applied for multiple comparisons.
Of 245 patients with rapid-cycling bipolar disorder (rapid-cycling bipolar I disorder, N = 191; rapid-cycling bipolar II disorder, N = 54) and a recent history of SUD, the demographics were similar. A significantly higher rate of panic disorder was observed in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder (odds ratio = 3.72, 95% CI = 1.66 to 8.32, p = .008). A significantly higher psychiatric composite score on the ASI was also found in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder even after Bonferroni adjustment (p = .0007). There were no significant differences between the subtypes in the rates of previous hospitalization or suicide attempt, early childhood verbal, physical, or sexual abuse, lifetime substance abuse or dependence, the number of SUDs or mood episodes in the last 12 months, and total or other subscale scores on ASI and GAS.
Except for the significantly higher rate of comorbid panic disorder and higher psychiatric composite scores on the ASI in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder, the other clinical variables were similar between the 2 groups.
PMCID: PMC4285700  PMID: 18588360
10.  The Early Longitudinal Course of Cognitive Deficits in Schizophrenia 
Cognitive impairment is a core feature of schizophrenia. However, the longitudinal course and pattern of this impairment, and its relationship to functional outcome is not fully understood. Among the likely factors in the persistence of cognitive deficits in schizophrenia are brain tissue changes over time, which in turn appear to be related to antipsychotic medication adherence.
Cognitive deficits are viewed as a core feature of schizophrenia primarily because cognitive deficits clearly exist before the onset of psychosis and can predict illness onset among those at high risk of developing the illness. Additionally, these deficits often persist during symptomatic remissions in patients, and are relatively stable across time both in patients and in individuals at risk for schizophrenia.
Despite clear evidence that cognitive impairment can predict functional outcome in chronic schizophrenia, results of studies examining this relationship in the early phase of psychosis have been mixed. Recent data, however, strongly suggest that interventions targeting early cognitive deficits may be crucial to the prevention of chronic disability, and thus should be a prominent target for therapy.
Finally, it is vital to keep schizophrenia patients consistently on their antipsychotic medications. A novel method of examining intracortical myelin volume indicated that the choice of antipsychotic treatment had a differential impact on frontal myelination. These data suggest that long acting injectable antipsychotic medication may prevent patients from declining further through a combination of better adherence and pharmacokinetics.
PMCID: PMC4081490  PMID: 24919168
11.  Length of Time between Onset of Childhood Sexual Abuse and Emergence of Depression in a Young Adult Sample 
Depression is the most common adult outcome of exposure to childhood sexual abuse (CSA). In this study, we retrospectively assessed the length of time from initial abuse exposure to onset of a major depressive episode.
A community-based survey of childhood experiences in 564 young adults (ages 18 to 22 years) conducted between 1997 and 2001 identified 29 right-handed female subjects with CSA but no other exposure to trauma. Subjects were interviewed for lifetime history and age of onset of Axis I disorders using the Structured Clinical Interview for DSM-IV Axis I Disorders.
Sixty-two percent (n = 18) of the sexual abuse sample met full lifetime criteria for major depression. Episodes of depression emerged, on average, 9.2 ± 3.6 years after onset of exposure to sexual abuse. Mean survival time from onset of abuse to onset of depression for the entire sample was 11.47 years (95% CI: 9.80 – 13.13 years). There was a surge in new cases between 12-15 years of age. Average time to onset of posttraumatic stress disorder was 8.0 ± 3.9 years.
Exposure to CSA appears to sensitize women to the development of depression, and to shift age of onset to early adolescence. Findings from this formative study suggest that clinicians should not interpret the absence of symptoms at the time of CSA as a sign of resilience. Continued monitoring of victims of CSA as they pass through puberty is recommended. Reasons for the time lag between CSA and depression are proposed along with potential strategies for early intervention.
PMCID: PMC4266432  PMID: 19358787
12.  Suicide, Hospital-Presenting Suicide Attempts, and Criminality in Bipolar Disorder: Examination of Risk for Multiple Adverse Outcomes 
The Journal of clinical psychiatry  2014;75(8):e809-e816.
To compare risks for suicidality and criminality in a national cohort of people diagnosed with bipolar disorder, and to assess how risk factor profiles differ between these outcomes.
We conducted 2 case-cohort studies using interlinked Swedish national registers. Primarily, using International Classification of Diseases (ICD) coding, we identified 15,337 people diagnosed with bipolar disorder, 1973–2009, matched by age and gender to 20 individuals per case sampled randomly from the general population. We estimated risks of suicide and hospital-presenting attempted suicide, and violent and nonviolent criminal offending. We separately assessed these risks among 14,677 unaffected siblings matched to a second general population sample.
22.2% of bipolar disorder cohort members engaged in suicidal or criminal acts after diagnosis. They were at greatly elevated risk for completed suicide (risk ratio = 18.8; 95% CI, 16.0–22.2), attempted suicide (risk ratio = 14.3; 95% CI, 13.5–15.2), violent crime (risk ratio = 5.0; 95% CI, 4.6–5.4), and nonviolent crime (risk ratio = 2.9; 95% CI, 2.8–3.1) compared with the general population. Elevations in risk were far less marked among the unaffected siblings than in the bipolar disorder cohort. Three factors independently predicted raised risk of all 4 adverse outcomes: if the first 2 patient episodes for bipolar disorder required admission, a history of attempted suicide, and a history of diagnosed alcohol/drug disorder. Criminal offending before bipolar diagnosis was an especially strong independent predictor of criminality after diagnosis.
The combined risk of suicidality or criminality is substantially elevated in both relative and absolute terms. Clinical prediction rules focusing on multiple vulnerabilities following onset of bipolar disorder, especially when there is history of attempted suicide, substance misuse disorders, or criminal offending, may improve risk management.
PMCID: PMC4226039  PMID: 25191918
13.  A Direct, Controlled, Blind Family Study of DSM-IV Pathological Gambling 
Pathological gambling is a major public health problem. We sought to examine the familiality of pathological gambling and determine patterns of familial aggregation of disorders.
We assessed probands with DSM-IV pathological gambling, controls, and their first-degree relatives. Detailed family history information was collected on relatives who were deceased or unavailable.
Ninety-five pathological gambling probands, 91 controls, and their 1,075 first-degree relatives over age 18 (537 relatives of pathological gambling probands, 538 relatives of controls) were evaluated between February 2005 and June 2010. Relatives were assessed blind to proband status. Best estimate diagnoses were assigned. Rates of lifetime pathological gambling (definite/probable) was significantly greater among the first-degree relatives of probands with pathological gambling than among comparison relatives (11% vs 1%, OR = 8.19, P < .001). The prevalence of pathological gambling and subclinical pathological gambling combined was 16% and 3% in case and control relatives, respectively (OR = 6.57, P < .001). Pathological gambling relatives had higher rates of major depression (OR = 1.49, P < .05), bipolar disorder (OR = 3.82, P < .05), any mood disorder (OR = 1.59, P < .05), social anxiety disorder (OR = 4.76, P < .01), any substance use disorder (OR = 1.47, P < .05), posttraumatic stress disorder (OR = 2.59, P < .05), and antisocial personality disorder (OR = 3.72, P < .001). Antisocial personality disorder (OR = 3.12, P < .01), social anxiety disorder (OR = 4.15, P < .01), and posttraumatic stress disorder (OR = 2.85, P < .05) were more frequent in case relatives independent of the presence of pathological gambling. Age at onset of pathological gambling in case probands (< 40 years/≥ 40 years) was not related to familiality in their first-degree relatives (OR = 1.03, P = .927).
Pathological gambling is familial. Mood and substance use disorders may emerge as a consequence of the pathological gambling or as a more complex syndrome. In contrast, antisocial personality disorder, social anxiety disorder, and posttraumatic stress disorder may share a common familial etiology with pathological gambling. The phenotype may extend beyond pathological gambling to include subclinical forms of the disorder.
PMCID: PMC4221079  PMID: 24500179
14.  Onset and Exacerbation of Obsessive-Compulsive Disorder in Pregnancy and the Postpartum Period 
The Journal of clinical psychiatry  2010;71(8):1061-1068.
The primary goal of this study was to examine the impact of pregnancy, childbirth and menstruation on the onset of obsessive-compulsive disorder (OCD) and/or exacerbation of OCD symptoms.
One hundred twenty-six women attending a university-based OCD clinic aged 18-69 years who met DSM-IV criteria for OCD according to the Structured Clinical Interview for DSM-IV Disorders were interviewed retrospectively to assess OCD onset and symptom exacerbation in relationship to reproductive events. Women were placed into two groups: ever pregnant (Preg) and never pregnant (NPreg). The Preg group was further subdivided into those who reported onset of OCD in the perinatal period (perinatal-related, PR) and those that denied onset related to pregnancy (non-perinatal-related, NR). Between groups comparisons were done using a Student’s t-test for continuous measures and categorical variables were assessed using the chi-square test.
Of the 76 women in the Preg group, 32.1% (N = 25) had OCD onset in the perinatal period (PR group), 15.4% in pregnancy, 15.4% at postpartum, and 1.3% following miscarriage. Out of 132 total pregnancies, 34.1% involved an exacerbation of symptoms, 22.0% involved an improvement in OCD symptoms, and 43.9% did not change symptom severity in women with pre-existing illness. Women in the PR group and women with perinatal worsening of pre-existing OCD were more likely to have premenstrual worsening of OCD symptoms compared to NR women (65.5% vs. 39.3%, p = 0.047).
Findings from this study provide additional evidence that pregnancy and childbirth are frequently associated with the onset of OCD or worsening of symptoms in those with pre-existing disorder. In addition, there appears to be continuity between OCD onset and/or exacerbation across the reproductive life cycle, at least with menstruation and pregnancy.
PMCID: PMC4204467  PMID: 20492843
15.  Treating nicotine dependence by targeting attention deficit hyperactivity disorder (ADHD): The role of ADHD severity and treatment response in a randomized controlled trial 
The Journal of clinical psychiatry  2013;74(10):983-990.
To determine whether treatment of ADHD with osmotic-release oral system methylphenidate (OROS-MPH) promotes abstinence from smoking among ADHD-smokers with greater severity of ADHD symptoms at baseline, or greater improvement in ADHD during treatment.
A randomized, double-blind, 11-week trial, was conducted between December 2005 and January 2008 at six clinical sites, sponsored by the National Drug Abuse Clinical Trials Network. Adult cigarette smokers, meeting DSM-IV criteria for ADHD, were randomly assigned to OROS-MPH (72 mg/day) (N = 127) or matching placebo (N = 128). All participants received nicotine patch (21 mg) and weekly individual smoking cessation counseling. Logistic regression was used to model prolonged abstinence from smoking (ascertained by self-report and breath carbon monoxide testing) as a function of treatment, baseline DSM-IV ADHD Rating Scale (ADHD-RS) score, change in ADHD-RS during treatment, and their interactions.
Treatment interacted with both ADHD-RS at baseline (p=0.01), and with change in ADHD-RS during treatment (p=0.008). Among patients with higher ADHD-RS scores (>36) at baseline and the most improvement in ADHD during treatment (ADHD-RS change score ≥24), 70% achieved abstinence on OROS-MPH, compared to 37% on placebo (p=.02). In contrast, among patients with the lowest ADHD-RS baseline scores (≤ 30), 30% achieved abstinence on OROS-MPH, compared to 61% on placebo (p=.02).
OROS-MPH, in combination with nicotine patch, may be an effective treatment for nicotine dependence among smokers with more severe ADHD, and more robust response of ADHD symptoms to the medication. OROS-MPH may be counterproductive among smokers with lower severity of ADHD.
PMCID: PMC3946795  PMID: 24229749
16.  A Gender Analysis of the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD): gender and age as predictors of response and treatment-associated changes in body mass index and metabolic measures 
The Journal of clinical psychiatry  2013;74(10):1003-1009.
Gender differences exist in psychiatric disorders; however gender has not been well studied in psychotic depression. This analysis of the largest clinical trial in psychotic depression examined the effects of age and gender on clinical characteristics and predictors of treatment outcome and treatment-associated changes in body mass index (BMI) and metabolic measures.
Analyses were performed on data from 259 subjects aged 18-93 in the double-blind randomized controlled trial of olanzapine plus sertraline (OLZ/SERT) vs. olanzapine plus placebo (OLZ/PBO) for psychotic depression (STOP-PD). Sociodemographic factors, clinical characteristics, treatment outcome and treatment-associated changes in BMI and metabolic measures were analyzed by gender and age.
Female gender was associated with divorced (χ2=5.3, d.f.=1, p=0.03) or widowed (χ2=8.1, d.f.=1, p=<0.01) marital status. Co-morbid anxiety disorders were more common in females than males (χ2=4.9, d.f.=1, p=0.03). Hallucinations(χ2=7.8, d.f.=1, p=0.005) and delusions with disorganization (t-test= −2.10, d.f. =257, p=0.04) were significantly associated with female gender as were higher cholesterol measures( χ2=7.15, d.f.=1, p=0.008).There were no significant interactions between treatment and gender in terms of change in BMI. Gender was not associated with treatment response.
This is the first analysis of gender and age as predictors of treatment outcome and treatment-associated changes in BMI and metabolic adverse effects in psychotic depression. Gender differences exist in patients with psychotic depression, most notably the presence of hallucinations. Female gender was associated with metabolic measures. Future studies with larger sample sizes may detect small gender differences in treatment outcome and treatment-associated changes in BMI and metabolic measures in psychotic depression.
PMCID: PMC3966190  PMID: 24229753
psychotic depression; clinical trial, gender differences; clinical characteristics; body mass index; metabolic measures
18.  Bioavailability of S-Adenosyl Methionine and Impact on Response in a Randomized Controlled Trial in Major Depressive Disorder 
To characterize the impact of S-adenosylmethionine (SAMe) on homocysteine, and potential risk of adverse cardiovascular effects, by examining plasma levels of SAMe, S-adenosylhomocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MHTF) in 35 of 73 patients from a 6-week double-blind randomized trial of SAMe augmentation in serotonin-reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010.
Subjects were randomized from 6/4/2004-8/8/2008 to adjunctive placebo or SAMe 800-1600 mg/day for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t-test) and between treatment arms (by independent samples t-test). Univariate analysis of variance and Fisher’s Protected Least Significant Difference were carried out to compare post-treatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediates, examined by linear regression (for change in HAM-D) and logistic regression (for response or remission).
We found significant differences in pre-treatment plasma levels of tHCY (p=0.03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (p=0.002) and SAH (p<0.0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Post-treatment plasma SAMe (p=0.0035), SAH (P<0.0001), and tHCY (p=0.0016) differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission.
Despite concerns about the impact that SAMe therapy may have on homocysteine, and risk of adverse cardiovascular effects, the lack of significant increase in tHCY after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution.
PMCID: PMC4156851  PMID: 22687580
SAMe; S-adenosylmethionine; bioavailability; depression; homocysteine; methionine; methyltetrahydrofolate
19.  Patient Preference for Psychological vs. Pharmacological Treatment of Psychiatric Disorders: A Meta-Analytic Review 
Models of evidence-based practice emphasize the consideration of treatment efficacy/effectiveness, clinical expertise, and patient preference in treatment selection and implementation. However, patient preference for psychiatric treatment has been understudied. The aim of this meta-analytic review was to provide an estimate of the proportion of patients preferring psychological treatment relative to medication for psychiatric disorders.
Data Sources
A literature search was conducted using PubMed, PsycINFO, and the Cochrane Collaboration Library through August, 2011 for studies written in English that assessed patient preferences for the treatment of psychiatric disorders.
Study Selection
Studies assessing the preferred type of treatment including at least one psychological treatment and one pharmacological treatment were included. Of the 641 articles initially identified, 34 met criteria for inclusion.
Data Extraction
Authors extracted relevant data including the proportion of participants reporting preference for psychological and pharmacological treatment.
Across studies, the proportion preferring psychological treatment was 0.75 (95% CI: 0.69 to 0.80), which was significantly higher than equivalent preference (i.e., higher than 0.50, p < .001). Sensitivity analyses suggested that younger patients (p < .05) and women (p < .01) were significantly more like to choose psychological treatment. A preference for psychological treatment was consistently evident in both treatment-seeking and unselected samples (ps < .05), but was somewhat stronger for the unselected samples.
Aggregation of patient preferences across diverse settings yielded a significant three-fold preference for psychological treatment relative to medication. Given the similar efficacy of these treatments for depression and anxiety, improving access to evidence-based psychological treatment is needed to connect more patients to their preferred treatment.
PMCID: PMC4156137  PMID: 23842011
20.  Randomized Controlled Trial to Reduce Cardiovascular Disease Risk for Patients with Bipolar Disorder: the Self-Management Addressing Heart Risk Trial (SMAHRT) 
The Journal of clinical psychiatry  2013;74(7):e655-e662.
Persons with bipolar disorder experience a disproportionate burden of medical conditions, notably cardiovascular disease (CVD), leading to impaired functioning and premature mortality. The study objective was to determine whether the Life Goals Collaborative Care (LGCC) intervention compared to enhanced usual care, reduced CVD risk factors and improved physical and mental health outcomes in VA patients with bipolar disorder.
Patients with ICD-9 diagnosis of bipolar disorder and >=1 CVD risk factor (n=118) enrolled in the Self-Management Addressing Heart Risk Trial conducted April 2008–May 2010, were randomized to LGCC (N=58) or enhanced usual care (N=60). LGCC included four weekly self-management sessions followed by tailored contacts combining health behavior change strategies, medical care management, registry tracking, and provider guideline support. Enhanced usual care included quarterly wellness newsletters sent over a 12-month period in addition to standard treatment.
Out of the 180 eligible patients identified for study participation, 134 were enrolled (74%) and 118 completed outcomes assessments (mean age = 53, 17% female, 5% African American). Mixed effects analyses comparing changes in 24-month outcomes among patients in LGCC (N=57) versus enhanced usual care (N=59) groups revealed that patients receiving LGCC had reduced systolic (Beta=−3.1, P=.04) and diastolic blood pressure (Beta=−2.1, P=.04) as well as reduced manic symptoms (Beta=−23.9, P=.01). LGCC had no significant impact on other primary outcomes (total cholesterol, physical health-related quality of life).
LGCC compared to enhanced usual care may lead to reduced CVD risk factors, notably through decreased blood pressure, as well as reduced manic symptoms.
PMCID: PMC4154058  PMID: 23945460
mental disorders; cardiovascular disease; collaborative care; health behaviors
21.  A Longitudinal Investigation of the Role of Self-Medication in the Development of Comorbid Mood and Drug Use Disorders 
The Journal of clinical psychiatry  2012;73(5):e588-e593.
To examine whether self-medication with drugs confers risk of comorbid mood and drug use disorders.
A longitudinal, nationally representative survey was conducted by the National Institute on Alcohol Abuse and Alcoholism. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) assessed DSM-IV psychiatric disorders, self-medication, and sociodemographic variables at two time points. A total of 34,653 adult, U.S. participants completed both waves of the survey. Wave 1 was conducted between 2001–2002 and Wave 2 interviews took place 3 years later (2004–2005). Logistic regression and population attributable fractions were calculated to obtain estimates of the association between self-medication and incident disorders.
Logistic regression analyses revealed that self-medication with drugs conferred a heightened risk of new-onset drug dependence among those with baseline mood disorders [adjusted odds ratio (AOR)=7.65; 95% confidence interval (CI) 3.70–15.82, p<.001], and accounted for over 25% of incident drug dependence disorders among people with mood disorders. Among those with comorbid mood and drug use disorders at baseline, self-medication with drugs was associated with the persistence of drug abuse (AOR=2.47; 95%CI=1.34–4.56, p<0.01), accounting for over one-fifth of the persistence of drug use disorders at three year follow-up.
Self-medication with drugs amongst individuals with mood disorders confers substantial risk of developing incident drug dependence, and is associated with the persistence of comorbid mood and drug use disorders. These results clarify a pathway that may lead to the development of mood and drug use disorder comorbidity, and indicate an at-risk population with potential points of intervention for prevention of comorbidity.
PMCID: PMC4151244  PMID: 22697205
Self-medication; mood disorders; drug dependence; comorbidity; epidemiology
22.  Effect of Psychostimulants on Brain Structure and Function in ADHD: A Qualitative Literature Review of MRI-Based Neuroimaging Studies 
To evaluate the impact of therapeutic oral doses of stimulants on the brains of ADHD subjects as measured by MRI-based neuroimaging studies (morphometric, functional, spectroscopy).
Data Sources
We searched PubMed and ScienceDirect through the end of calendar year 2011 using the keywords: 1) “psychostimulants” or “methylphenidate” or “amphetamine”, and 2) “neuroimaging” or “MRI” or “fMRI”, and 3) “ADHD” or “ADD” or “Attention-Deficit/Hyperactivity Disorder” or “Attention Deficit Hyperactivity Disorder”.
Study Selection
We included only English language articles with new data that were case or placebo-controlled and examined ADHD subjects on and off psychostimulants (as well as 5 relevant review papers).
Data Extraction
We combined details of study design and medication effects in each imaging modality.
We found 29 published studies that met our criteria. These included 6 structural MRI, 20 functional MRI studies and 3 spectroscopy studies. Methods varied widely in terms of design, analytic technique, and regions of the brain investigated. Despite heterogeneity in methods, however, results were consistent. With only a few exceptions, the data on the effect of therapeutic oral doses of stimulant medication suggest attenuation of structural and functional alterations found in unmedicated ADHD subjects relative to findings in Controls.
Despite the inherent limitations and heterogeneity of the extant MRI literature, our review suggests that therapeutic oral doses of stimulants decrease alterations in brain structure and function in subjects with ADHD relative to unmedicated subjects and Controls. These medication-associated brain effects parallel, and may underlie, the well-established clinical benefits.
PMCID: PMC3801446  PMID: 24107764
Stimulants; ADHD; Brain; MRI
23.  Risk of Suicidal Behavior With Antidepressants in Bipolar and Unipolar Disorders 
To examine the risk ofsuicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar n, and unipolar major depressive disorders.
A 27-year longitudinal (1981-2008) observational study ofmood disorders (Research Diagnostic Criteria diagnoses based on Schedule Dr Afi:ctive Disorders and Schizophrenia and review ofmedical records) was used to evaluate antidepressants and risk Dr suicidal behavior. Mixed-efi:cts logistic regression models examined propensity Dr antidepressant exposure. Mixed-efi:cts swvival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior.
Five US academic medical centers.
Analyses of206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1 ,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2, 745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confinned that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-elects swvival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P < .001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = −2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder.
Based on obsetVational data adjusted Dr propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.
PMCID: PMC4142755  PMID: 25093469
24.  A prospective trial of customized adherence enhancement plus long-acting injectable antipsychotic medication in homeless or recently homeless individuals with schizophrenia or schizoaffective disorder 
The Journal of clinical psychiatry  2013;74(12):1249-1255.
Treatment non-adherence in people with schizophrenia is associated with relapse and homelessness. Building upon the usefulness of long-acting medication, and our work in psychosocial interventions to enhance adherence, we conducted a prospective uncontrolled trial of customized adherence enhancement (CAE) plus long-acting injectable antipsychotic (LAI) using haloperidol decanoate in 30 homeless or recently homeless individuals with schizophrenia and schizoaffective disorder.
Participants received monthly CAE and LAI (CAE-L) for 6 months. Primary outcomes were adherence as measured by the Tablets Routine Questionnaire (TRQ) and housing status. Secondary outcomes included psychiatric symptoms, functioning, side effects, and hospitalizations.
Mean age of participants was 41.8 years (SD 8.6), mainly minorities (90% African-American) and mainly single/never married (70%). Most (97%) had past or current substance abuse, and had been incarcerated (97%). Ten individuals (33%) terminated the study prematurely. CAE-L was associated with good adherence to LAI (76% at 6 months) and dramatic improvement in oral medication adherence, which changed from missing 46% of medication at study enrollment to missing only 10% at study end (p = 0.03). There were significant improvements in psychiatric symptoms (p<.001) and functioning (p<.001). Akathisia was a major side effect with LAI.
While interpretation of findings must be tempered by the methodological limitations, CAE-L appears to be associated with improved adherence, symptoms, and functioning in homeless or recently homeless individuals with schizophrenia or schizoaffective disorder. Additional research is needed on effective and practical approaches to improving health outcomes for homeless people with serious mental illness.
PMCID: PMC4129952  PMID: 24434094
Homelessness; schizophrenia; schizoaffective disorder; treatment adherence; antipsychotic medication; haloperidol
25.  Response to Antidepressant Medications in Late Life Depression, Across the Spectrum of Cognitive Functioning 
The Journal of clinical psychiatry  2014;75(2):e100-e107.
Depression in later life frequently coexists with cognitive impairment. To inform clinical management of these co-occurring conditions, we examined the hypotheses that, relative to cognitively normal elders meeting DSM-IV criteria for major depression, those with cognitive impairment would require greater intensity of pharmacotherapy to reach criteria for response, and take longer to respond.
Using data from the recent Maintenance Therapies in Late Life Depression (MTLD-3) study, we conducted a series of secondary analyses examining the implications of cognitive impairment for short-term, open-trial pharmacotherapy of late-life depression (major depression in individuals aged 65 years and older). This short-term treatment trial consisted of three steps: initial treatment with an SSRI, subsequent switch to an SNRI if patient did not meet criteria for response, and addition of an atypical antipsychotic (AAP) for non-response to SNRI monotherapy. The first subject entered the MTLD-3 protocol in April 2004, and the last subject exited the protocol in September 2009. We examined data for participants who completed the acute phase of MTLD-3 as responders and received a consensus cognitive diagnosis (N=153) from the University of Pittsburgh Alzheimer’s Disease Research Center, based on National Alzheimer Coordinating Center Uniformed Data Set criteria. We divided participants into three groups, based on cognitive diagnosis: normal cognitive function (N=74), Mild Cognitive Impairment (N=60), and dementia (N=19). For each group, we calculated the proportion of participants who required first (SSRI), second (SNRI), or third-step (add-on AAP) treatment to meet criteria for clinical response (HRSD-17 score ≤ 10 for three consecutive weeks). We compared time to response across groups, and examined patterns of response by inspection of weekly HRSD-17 scores. Finally, we examined correlates of non-response.
The three groups did not differ significantly with respect to time to response (p=0.84), trajectories to response, or intensity of antidepressant pharmacotherapy (p=0.68). Non-response was more strongly correlated with longer index MDE duration (p=0.0015), presence of recurrent depression (p=0.002), and younger current age (p=0.047), rather than with cognitive status (p=0.61).
Cognitive status does not appear to impact short-term pharmacotherapy response variability in individuals whose depression responds to treatment with open-trial antidepressant pharmacotherapy delivered in a supportive, university-based medication clinic.
PMCID: PMC4060895  PMID: 24602256
late life depression; mild cognitive impairment; dementia; treatment response variability

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