[Show abstract][Hide abstract] ABSTRACT: To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression.
In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups.
The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04).
This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation.
clinicaltrials.gov Identifier: NCT00012558.
The Journal of Clinical Psychiatry 04/2010; 71(4):372-80. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since bipolar disorder (BPD) patients have high rates of comorbid substance abuse, and the temporal relationships involved are unclear, we evaluated the sequencing of specific substance use and affective morbidity.
Prospective follow-up (4.7 years) of 166 first-episode DSM-IV type I BPD patients with reliable, standardized assessments provided data for longitudinal analysis of temporal distribution of alcohol and cannabis use versus manic or depressive episodes or symptoms, using generalized estimating equation regression modeling.
By quarters, cannabis use selectively and strongly preceded and coincided with mania/hypomania, and alcohol use preceded or coincided with depression, whereas substance use was unassociated with mood states in preceding quarters.
These preliminary findings suggest potentially predictive temporal associations, in which the abuse of cannabis or alcohol anticipated or corresponded with, but did not follow, affective morbidity, including selective association of cannabis with mania and alcohol with depression.
[Show abstract][Hide abstract] ABSTRACT: To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.
Journal of Psychiatric Research 08/2008; 42(8):605-11. · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Risks of life-threatening behaviors are high among bipolar disorder (BPD) patients, but early rates and associated risk factors for suicides and accidents remain ill-defined.
We assessed 216 DSM-IV BP-I patients prospectively for 4.2 years from first-lifetime hospitalization, using ordinal logistic-regression to estimate risks and associated demographic and clinical factors among risk-groups with:  no suicidal ideation, acts, or accidents,  suicidal ideation only,  suicides and attempts,  accidents, and  both suicidal acts and accidents.
Suicidal thoughts or acts were identified in 127/216 subjects/4.2 years (14%/year), including suicidal ideation in 88 (9.7%/year), and acts in 39 (4.3%/year: 38 attempts [17.6%/year], 1 suicide [0.11%/year]); 87% of acts occurred within a year of a first-episode. Life-threatening accidents occurred in 20 cases (2.2%/year) with a mean latency of 3.8 years, including 12 with suicidal ideation or attempts (60% co-occurrence of accidents and suicidality); alcohol was implicated in 25% of accidents. The 53 cases of violent behaviors (5.84%/year) included a fatal car-wreck and a suicide, for a mortality risk of 0.22%/year (2/216/4.2 years). Suicidality was associated with initial mixed-state, proportion of follow-up weeks in mixed-states or depression, and prior suicide attempts; accidents were associated selectively with initial mania or psychosis, later mania or hypomania, and alcohol abuse. Violent acts also were associated with use of more psychotropic medicines/person, and with use of antipsychotics or sedative-anxiolytics.
Treatment was clinical and uncontrolled, illness relatively severe, and statistical power limited.
Early in BP-I disorder, risks of suicidal acts and accidents were high, inter-related, and associated with particular types of initial and later morbidity, suggesting some predictability and potential for preventive intervention.
Journal of Affective Disorders 03/2008; 106(1-2):179-84. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since the onset, prevalence, and course of specific psychopathological features rarely have been analyzed simultaneously from the start of dissimilar psychotic illnesses, we compared symptom-clusters in first-episode DSM-IV affective and non-affective psychotic disorders.
Subjects (N=377) from the McLean-Harvard First Episode Project hospitalized for first-lifetime primary psychotic illnesses were followed prospectively for 2 years to verify stable DSM-IV diagnoses. We ascertained initial symptoms from baseline SCID and clinical assessments, applying AMDP and Bonn psychopathology schemes systematically to describe a broad range of features. Final consensus diagnoses were based on intake and follow-up SCID assessments, family interviews, and medical records. Factor-analytic methods defined first-episode symptom-clusters (Factors), and multiple-regression modeling related identified factors to initial DSM-IV diagnoses and to later categories (affective, non-affective, or schizoaffective disorders).
Psychopathological features were accommodated by four factors: I represented mania with psychosis; II a mixed depressive-agitated state; III an excited-hallucinatory-delusional state; IV a disorganized-catatonic-autistic state. Each factor was associated with characteristic prodromal symptoms. Factors I and III associated with DSM-IV mania, II with major depression or bipolar mixed-state, III negatively with delusional disorder, IV with major depression and negatively with mania. Factors I and II predicted later affective diagnoses; absence of Factor I features predicted non-affective diagnoses, and no Factor predicted later schizoaffective diagnoses.
The findings contribute to descriptive categorizations of psychopathology from onset of dissimilar psychotic illnesses. This approach was effective in identifying and subtyping affective psychotic disorders early in their clinical evolution, but non-affective and schizoaffective conditions appear to be more complex and unstable.
Journal of Psychiatric Research 12/2007; 41(9):724-36. · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antidepressant use during pregnancy and the peripartum period is common despite the absence of clear evidence-based guidelines to direct clinical use of these compounds.
We compared obstetrical and neonatal outcomes as recorded in medical records among 84 pregnant women with major depressive or anxiety disorders (DSM-IV criteria) who took antidepressants during pregnancy (cases) versus a 2:1 age- and parity-matched control group of 168 unexposed women. Women in the case group had sought psychiatric consultation regarding the use of medication from the Perinatal and Reproductive Psychiatry Program at the Massachusetts General Hospital between 1996 and 2000.
There were no significant differences among cases versus controls and their offspring, with respect to various neonatal and obstetrical outcomes, including gestational age and weight, although 1-minute Apgar scores were slightly lower in exposed infants. Admissions to the special care nursery were more frequent, but briefer and based on relatively minor indications, among case newborns. There were no significant differences in neonatal outcomes between exposures to serotonin reuptake inhibitor (SRI) and tricyclic (TCA) antidepressants.
This retrospective cohort study found no evidence of major increases in risk of adverse obstetrical or neonatal outcomes following prenatal exposure to antidepressants, nor between SRIs and TCAs. Larger, prospective studies with specific neurobehavioral measures are required to resolve current uncertainties about safe and effective use of antidepressants by pregnant women.
The Journal of Clinical Psychiatry 09/2007; 68(8):1284-9. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the relationships among depressive signs and symptoms and left versus right temporal-parietal cerebral blood volumes (CBVs) in elderly patients with a primary complaint of memory loss.
Total Geriatric Depression Scale Short Form (GDS-SF) scores, left and right temporal-parietal cerebral blood volume values, and other prospectively recorded data were obtained via chart review of 24 patients aged >/=65 years, evaluated between 1995 and 2000 at McLean Hospital for a primary complaint of memory loss. Multivariate regression analyses were carried out with GDS-SF total scores as outcome variables, with CBV values as explanatory factors and with several patient characteristics as covariates.
Depressive symptoms, as measured by the GDS-SF, were significantly associated with decreased left/right temporal-parietal CBV ratios (beta regression coefficient = -20.7; t [df = 22] = -2.96, p = 0.007). These findings remained statistically significant after controlling for age, sex, Mini-Mental State Exam (MMSE) score, years of education, years of memory loss, and handedness (beta regression coefficient = -16.7; t [df = 16] = -2.67, p = 0.017).
In this study, severity of depressive symptoms as measured by the GDS-SF in patients >/=65 years old who presented with a primary complaint of memory loss was associated with decreased left/right temporal-parietal CBV ratios, independently of age, sex, MMSE score, years of education, years of memory loss, and handedness. These findings suggest that in the presence of cognitive decline, increased depressive signs and symptoms may be associated with decreased left/right temporal-parietal CBV ratios.
American Journal of Geriatric Psychiatry 08/2007; 15(7):604-10. · 4.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Specific symptom dimensions have been used to establish phenotypic subgroups in recent genetic studies of bipolar disorder. In preparation for a genetic linkage study of childhood-onset bipolar disorder (COBPD), we conducted an exploratory analysis of the concordance of prominent symptom dimensions between sibling pairs (N=260) who screened positive for COBPD. This report presents data on the potential usefulness of these dimensions in genotyping.
A principal components factor analysis was conducted on the symptoms of 2795 children who screened positive for COBPD on the Child Bipolar Questionnaire (CBQ). The resulting factors were used in a concordance analysis between 260 proband/sibling pairs and 260 proband/matched comparison pairs.
Ten factors were extracted. The strongest concordance coefficients (rho) between probands and siblings, and the widest contrasts between proband/sibling vs. proband/comparison pairs, were for Factor 9 (Fear of harm), Factor 5 (Aggression), Factor 10 (Anxiety), Factor 4 (Sensory sensitivity), Factor 6 (Sleep-wake cycle disturbances), and Factor 2 (Attention/Executive function deficits). Based on factor loadings and multivariate analyses, CBQ items were selected for a "Core Index" subscale that had a robust concordance estimate in the sibpair group (rho=0.514, 95% CI 0.450-0.577) as compared to the proband-matched comparison group (rho=0.093, 95% CI 0.008 to 0.178).
Research diagnostic interviews (K-SADS P/L) were conducted to confirm bipolar diagnosis in only a subsample (N=100) of the children whose data were used for the concordance analysis.
Our data suggest a profile of heritable clinical dimensions in addition to classic mood symptomatology in COBPD. These features may represent a more homogeneous phenotypic subtype of COBPD that may prove more useful for delineating the neurobiology and genetics of the disorder than standard diagnostic models.
Journal of Affective Disorders 05/2007; 99(1-3):27-36. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bipolar disorders are prevalent major illnesses with high rates of morbidity, comorbidity, disability, and mortality. A growing number of psychotropic drugs are used to treat bipolar disorder, often off-label and in untested, complex combinations.
To quantify utilization rates for psychotropic drug classes, this study used the 2002-2003 U.S. national MarketScan research databases to identify 7,760 persons with ICD-9 bipolar disorder subtypes. Survival analysis was used to estimate times until initial monotherapies were augmented, changed, or discontinued.
The most commonly prescribed first drug class was antidepressants (50% of patients), followed by mood stabilizers (25%: anticonvulsants, 17%, and lithium, 8%), sedatives (15%), and antipsychotics (11%). At study midpoint only 44% of patients were receiving monotherapy. Those receiving monotherapy were ranked by initial drug prescribed and percentage of patients (bipolar I and bipolar II): antidepressants (55% and 65%), lithium (51% and 41%), antipsychotics (32% and 31%), anticonvulsants (28% and 29%), and sedatives (28%, 25%). Median time to adding another psychotropic was 2.5-times less than median time to changing the initial treatment (16.4 compared with 40.9 weeks), and stopping was rare. Median weeks until therapy was changed in any way for 25% of patients was as follows: lithium, 29 weeks; antidepressants, 13; anticonvulsants, 13; antipsychotics, 13; and sedatives, 9.
Antidepressants were the first-choice agent twice as often as mood stabilizers. Lithium was sustained longer than monotherapy with other mood stabilizers. Time to augmentation was much shorter than time to change or discontinuation.
[Show abstract][Hide abstract] ABSTRACT: To update and extend comparisons of rates of suicides and suicide attempts among patients with major affective disorders with versus without long-term lithium treatment.
Broad searching yielded 45 studies providing rates of suicidal acts during lithium treatment, including 34 also providing rates without lithium treatment. We scored study quality, tested between-study variance, and examined suicidal rates on versus off lithium by meta-analytic methods to determine risk ratios (RRs) and 95% confidence intervals (CI).
In 31 studies suitable for meta-analysis, involving a total of 85,229 person-years of risk-exposure, the overall risk of suicides and attempts was five times less among lithium-treated subjects than among those not treated with lithium (RR = 4.91, 95% CI 3.82-6.31, p < 0.0001). Similar effects were found with other meta-analytic methods, as well as for completed versus attempted suicide, and for bipolar versus major mood disorder patients. Studies with higher quality ratings, including randomized, controlled trials, involved shorter exposures with somewhat lesser lithium superiority. Omitting one very large study or those involving lithium-discontinuation had little effect on the results. The incidence-ratio of attempts-to-suicides increased 2.5 times with lithium-treatment, indicating reduced lethality of suicidal acts. There was no indication of bias toward reporting positive findings, nor were outcomes significantly influenced by publication-year or study size.
Risks of completed and attempted suicide were consistently lower, by approximately 80%, during treatment of bipolar and other major affective disorder patients with lithium for an average of 18 months. These benefits were sustained in randomized as well as open clinical trials.
[Show abstract][Hide abstract] ABSTRACT: The Child Bipolar Questionnaire (CBQ) is a rapid screener with a Core Index subscale of symptom dimensions frequently reported in childhood-onset bipolar disorder (BD) and scoring algorithms for DSM-IV BD, with and without attention-deficit/hyperactivity disorder (ADHD), and the proposed Narrow, Broad, and Core phenotypes. This report provides preliminary data on the reliability and validity of the CBQ.
Test-retest and inter-rater reliability of the CBQ were assessed. The ability of CBQ screening diagnoses and of the CBQ Core Index subscale to effectively predict diagnostic classification by structured interview was assessed using the K-SADS P/L.
Preliminary test-retest data showed excellent reliability for both the CBQ total score (r = 0.82) and the Core Index subscale (r = 0.86). Preliminary validity data was also promising. CBQ screening algorithms performed with a specificity of 97% and a sensitivity of 76% in classifying subjects with K-SADS P/L diagnosis of BD vs. no BD. The Core Index subscale had excellent agreement with K-SADS P/L diagnosis (k = 0.84) in classifying BD, ADHD-only, and no diagnosis and demonstrated 100% sensitivity and 86% specificity in classifying BD vs. no BD.
This preliminary data is from a sample enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse.
The CBQ shows potential for rapid and economically feasible identification of possible childhood-onset BD cases as defined by DSM-IV criteria as well as by alternate disease phenotypes. Further validation studies will focus on inpatient and outpatient samples with a broader range of variability.
Journal of Affective Disorders 11/2006; 95(1-3):149-58. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examines the efficacy of a short-term individual therapy, Manual Assisted Cognitive Treatment (MACT), which was developed to treat parasuicidal (suicidal or self-harming) patients. In this trial, MACT was modified to focus on deliberate self-harm (DSH) in patients with borderline personality disorder (BPD). Thirty BPD patients who were engaged in DSH while in ongoing treatments, i.e., treatment-as-usual (TAU), were randomly assigned to receive MACT (N = 15) or not. DSH and level of suicide ideation were assessed at the baseline, at completion of the MACT intervention, and six months later. Results indicated that MACT was associated with significantly less frequent DSH upon completion of the intervention and with significantly decreased DSH frequency and severity at the six months follow-up. Moreover, MACT's contribution to reducing DSH frequency and severity was greater than the contribution by the amount of concurrent treatments. In contrast, MACT did not affect the level of suicide ideation and time-to-repeat of DSH. In conclusion, MACT seems to be a promising intervention for DSH in patients with BPD. More definitive studies are needed.
Journal of Personality Disorders 11/2006; 20(5):482-92. · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As substance use disorders (SUD) are common in schizophrenia patients, we tested the hypothesis that comorbid patients (SUD[+]) have more positive vs. negative symptoms than non-comorbid (SUD[-]) patients. From reports identified by literature-searching we compared Positive and Negative Syndrome Scale (PANSS) ratings in schizophrenia patients with and without SUD using meta-analytic methods. Among 9 comparisons (N=725 subjects), SUD[+] patients were more often men, and abused alcohol>cannabis>cocaine. SUD[+] patients had very significantly higher PANSS-positive, and lower PANSS-negative scores. Comorbid SUD in schizophrenia patients was associated with male sex and higher PANSS positive to lower negative scores. Cause-effect relationships remain to be clarified.
Schizophrenia Research 09/2006; 86(1-3):251-5. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exponential advances have been made regarding computer/Internet technology in the past decade. This growth, in large part, can be attributed to greater access to, affordability of, and anonymity while on the computer. However, this progress has also produced negative psychological issues. Problematic Internet-enabled sexual behavior (IESB) has increasingly affected individuals' family relationships, work productivity, and academic success. This article is the first-known, empirically based outcome study regarding the effectiveness of group therapy treatment for men with problematic IESB. These closed-groups, which ran for 16 weeks, used a combination of Readiness to Change (RtC), Cognitive Behavioral Therapy (CBT), and Motivational Interviewing (MI) interventions. Five groups were analyzed for this paper (yielding a total N of 35), with the average member's age being 44.5 years old. Three different scales (the Orzack Time Intensity Survey, the BASIS-32, and the BDI) were used to track participants' progress across time. The results demonstrated that this group treatment intervention significantly increased members' quality of life and decreased the severity of their depressive symptoms. However, the protocol failed to reduce participants' inappropriate computer use. Regarding comorbidity, the results showed the following: members in the "anxiety" category responded best to the current treatment, those in the "mood" cluster responded relatively positively, and those in the "A-D/HD" category failed to respond significantly. It is clear from this report that more attention must be focused on the treatment of problematic IESB, as opposed to exploratory studies.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine the most clinically relevant baseline predictors of time to remission for patients with borderline personality disorder.
A total of 290 inpatients meeting criteria for both the Revised Diagnostic Interview for Borderlines and DSM-III-R for borderline personality disorder were assessed during their index admission with a series of semistructured interviews and self-report measures. Diagnostic status was reassessed at five contiguous 2-year time periods. Discrete survival analytic methods, which controlled for baseline severity of borderline psychopathology and time, were used to estimate hazard ratios.
Eighty-eight percent of the patients with borderline personality disorder studied achieved remission. In terms of time to remission, 39.3% of the 242 patients who experienced a remission of their disorder first remitted by their 2-year follow-up, an additional 22.3% first remitted by their 4-year follow-up, an additional 21.9% by their 6-year follow-up, an additional 12.8% by their 8-year follow-up, and another 3.7% by their 10-year follow-up. Sixteen variables were found to be significant bivariate predictors of earlier time to remission. Seven of these remained significant in multivariate analyses: younger age, absence of childhood sexual abuse, no family history of substance use disorder, good vocational record, absence of an anxious cluster personality disorder, low neuroticism, and high agreeableness.
The results of this study suggest that prediction of time to remission from borderline personality disorder is multifactorial in nature, involving factors that are routinely assessed in clinical practice and factors, particularly aspects of temperament, that are not.
American Journal of Psychiatry 06/2006; 163(5):827-32. · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bipolar disorder (BPD) is often comorbid with obsessive-compulsive (OCD) and other anxiety disorders, but the impact of such comorbidity on long-term outcome has not been evaluated systematically.
Extensive follow-up assessments were carried out at 4.3 years after index hospitalizations in a mixed BPD-OCD group (N=20) compared to matched groups with BPD (N=22) or OCD (N=20) alone.
At follow-up, ratings of functional status were similar across groups. Rehospitalizations were similar among BPD-OCD and BPD subjects, but 2.9-times more frequent among comorbid than OCD patients. OCD symptoms averaged 150% more severe in OCD than comorbid subjects, and were not measured in BPD subjects.
Despite potential sampling bias with previously hospitalized subjects, the findings suggest that comorbid BPD-OCD patients may be clinically more similar to BPD than OCD patients, and that BPD-OCD comorbidity may not negatively impact the long-term clinical outcome.
Human Psychopharmacology Clinical and Experimental 05/2006; 21(3):189-93. · 2.10 Impact Factor