Laszlo Gyulai | University of Pennsylvania (original) (raw)
Papers by Laszlo Gyulai
Journal of Cerebral Blood Flow & Metabolism, 1987
The objective of this study was to evaluate simultaneous31P/1H nuclear magnetic resonance (NMR) s... more The objective of this study was to evaluate simultaneous31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (Pao220 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO220 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 μmol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metab...
OBJECTIVES Our primary aim was to describe unique correlates of functioning in bipolar disorder (... more OBJECTIVES Our primary aim was to describe unique correlates of functioning in bipolar disorder (BD). EXPERIMENTAL DESIGN The study included the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Patients were 41.9 +/- 12.7 years old, and diagnosed with bipolar I, II or NOS, verified by structured interview. Overall functionality was determined by the Range of Impaired Function Tool (LIFE-RIFT). Stepwise multiple regression analysis tested the non-redundant-independent-association of 28 variables on functioning. PRINCIPAL OBSERVATIONS Severity of depression symptoms was significantly and uniquely correlated with impaired functioning in the context of a wide variety of demographic and clinical variables, contributing 60.9% to the total variance in overall functioning (ss = 0.254, p = 0.0001). Substantial variance in function remains unexplained. CONCLUSIONS Intensity of depressive symptoms is the major determinant of impaired f...
Biological Psychiatry, 1991
Measurements of the lithium concentration in the occipital pole of the head and calf muscle of ni... more Measurements of the lithium concentration in the occipital pole of the head and calf muscle of nine patients with bipolar disorder in remission were performed using in vivo lithium-7 nuclear magnetic resonance spectroscopy (7Li NMR). 7Li NMR measurements were performed on a 1-m-bore, 1.85-T, superconducting magnet supplemented with a multinuclear spectrometer, using l l.5-cm-diameter surface coils. The average lithium concentration in the occipital pole was 0.36 +_ 0.10 mEq/L, whereas in the muscle it was 0.50 +__ O. 17 mEqlL, both lower than the average serum lithium concentration (0.79 +_ 0.23 mEqlL). The average brain/serum lithium concentration ratio was 0.47 +_ 0.12 whereas the average muscle~serum lithium concentration ratio was 0.66 +_ 0.20. There was a positive correlation between the brain versus serum and brain versus muscle lithium concentrations. The hypothesis is advanced that the minimal effective concentration of brain lithium concentration for maintenance treatment of bipolar disorder is around 0.2-0.3 mEq/L.
Journal of Affective Disorders, 2001
Background: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the cour... more Background: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the course of illness in otherwise refractory affective disorders. This collaborative study investigates whether T4 augmentation for a minimum of 12 months decreases bone mineral density (BMD) in 26 pre-and post-menopausal women with affective disorder. Methods: We measured BMD at the femoral neck, Ward's triangle, trochanter and lumbar vertebrae (L1-L4) in 13 premenopausal and 13 2 postmenopausal women with affective disorder using dual energy X-ray absorptiometry. BMD was expressed as g / cm and as a Z-score, calculated using bone density data from the international reference population standard. Results: The Z-scores for the pre-and post-menopausal women were within the reference range of the age and sex matched population standard. BMD for the composite group also did not differ either from the population standard. BMD in the lumbar spine and hip did not differ significantly between the pre-and post-menopausal groups. However, there were a relatively high number of postmenopausal patients with BMDs one S.D. lower than the population standard. Limitations: This is a cross-sectional study with a relatively small sample size. Conclusions: The study demonstrates that T4 augmentation treatment does not reduce BMD to a clinically significant degree in many women with affective disorder. However, the resilience of bone structure to T4 treatment may vary with site and menopausal status. This study underscores the need for regular assessment of BMD during adjunctive thyroid treatments for affective disorder, especially in postmenopausal women.
Biological Psychiatry, 1997
The regional distribution of 1-123 iofetamine (IMP) in the brain of 12 patients with rapid cyclin... more The regional distribution of 1-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 rain after injection of 3-4 mCi ofi-123 labeled lMP. The 1-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal lobe dysfunction in bipolar disorder.
Journal of Psychiatric Research, 2005
While the prevalence of bipolar disorder I is similar between men and women, the clinical course ... more While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes. Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women. The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle. The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.
International Journal of Psychiatry in Clinical Practice, 2005
Background. In spite of widespread recognition of the importance of maintenance treatment for bip... more Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.
Psychiatry Research, 2005
This prospective, longitudinal study investigated the frequency and pattern of mood changes betwe... more This prospective, longitudinal study investigated the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. Eighty patients with bipolar disorder selfreported mood and psychiatric medications daily for 3 months using a computerized system (ChronoRecord) and returned 8662 days of data. Of the total group of 80 patients, 47 took antidepressants; 33 did not. Patients taking antidepressants reported depression twice as frequently (29% of days vs. 13.8% of days). In both groups, two-thirds of all mood changes over a 1-, 2-and 3day period were small, between À5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (N10 on a 100-point scale) or in switches between depression and mania (0.7% if not taking antidepressants vs. 0.9% if taking), independent of diagnosis of bipolar I or II. Eighty-nine percent of patients taking antidepressants were also taking mood stabilizers. In this naturalistic setting, no significant difference between the rate of switches to mania or rapid cycling was found between those taking and not taking antidepressants, regardless of diagnosis. The primary difference in pattern between the groups was the time spent in depressed or normal mood, with minor daily mood variations.
Bipolar Disorders, 2010
Young RC, Schulberg HC, Gildengers AG, Sajatovic M, Mulsant BH, Gyulai L, Beyer J, Marangell L, K... more Young RC, Schulberg HC, Gildengers AG, Sajatovic M, Mulsant BH, Gyulai L, Beyer J, Marangell L, Kunik M, Ten Have T, Bruce ML, Gur R, Marino P, Evans JD, Reynolds CF III, Alexopoulos GS. Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD. Bipolar Disord 2010: 12: 56–67. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S.Aim: This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients.Method: There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions.Results: Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria.Conclusions: A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.
Acta Psychiatrica Scandinavica, 2006
Objective: To investigate seasonal and regional effects on bipolar I and II patients.Method: Th... more Objective: To investigate seasonal and regional effects on bipolar I and II patients.Method: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region.Results: A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients.Conclusion: The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.
Biological Psychiatry, 2003
Background: There is debate whether patients with rapid-cycling bipolar disorder (BD) are predisp... more Background: There is debate whether patients with rapid-cycling bipolar disorder (BD) are predisposed to thyroid axis abnormalities and whether this may contribute to development of rapid mood shifts. Using lithium carbonate as a challenge to the hypothalamic-pituitary-thyroid (HPT) system, we determined whether patients with rapidcycling BD are sensitive to the "antithyroid" properties of lithium. Methods: We studied the response to thyrotropin-releasing hormone (TRH) of HPT system hormones in 20 medication-free patients with rapid-cycling BD and compared these measurements with those of 20 healthy ageand gender-matched control subjects. The same measurements were repeated after both groups had received lithium carbonate for 4 weeks in sufficient doses to maintain blood levels between .7-1.2 mEq/L. Results: At baseline, the results of thyroid function tests, including the TRH challenge test, did not differ between patients and control subjects. After treatment with lithium, serum concentrations of thyroxine significantly decreased, whereas basal thyrotropin (TSH) and ⌬TSH max significantly increased in both patients and control subjects; however, patients had significantly higher ⌬TSH max after TRH stimulation. More patients than control subjects developed laboratory evidence consistent with grade III hypothyroidism after lithium treatment. Conclusions: Rapid-cycling BD is associated with a latent hypofunction of the HPT system. This dysfunction becomes manifest with short-term lithium challenge. Biol Psychiatry 2003;53:899 -905
Archives of General Psychiatry, 2000
Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effec... more Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.
Biological Psychiatry, 1997
To describe the relationship between mood and body weight, we analyzed 122 consecutive days of da... more To describe the relationship between mood and body weight, we analyzed 122 consecutive days of data from a 52-year-old woman with rapid cycling bipolar disorder, type II. The patient completed a daily log of selfreported mood, and weighed and recorded her weight daily. Mood and body weight were highly correlated (r = 0.60), and a decrease in mood preceded a decline in body weight by 3 days. Reports of loss of appetite on the Hamilton Depression Rating Scale also corresponded to periods of weight loss. There was a negligible difference in the patient's resting metabolic rate between a period of depression (1628 kcal/day) and of euthymia (1724 kcal/day). The association between depression and weight loss was primarily mediated by decreased food intake. Such patients should provide an excellent opportunity to study the regulation of body weight with affective illness.
American Journal of Geriatric Psychiatry, 2005
The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains u... more The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains understudied. Authors retrospectively examined response to lamotrigine, lithium, and placebo in older (>or=age 55) adults with Bipolar I disorder (DSM-IV) who participated in two mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. In all, 588 patients received double-blind lamotrigine (LTG, 100 mg-400 mg/day), lithium (Li, 0.8 mEq/L-1.1 mEq/L), or placebo (PBO); data from 98 older adults (LTG: 33, Li: 34, PBO: 31) were examined. Mean modal total daily doses were LTG 240 mg and Li 750 mg. LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. Lamotrigine and lithium may be effective and well-tolerated maintenance therapies for older adults with Bipolar I depression.
Neuropsychopharmacology, 2003
Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recen... more Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.
Archives of General Psychiatry, 2007
Context: Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipola... more Context: Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
American Journal of Psychiatry, 2008
In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of ... more In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.
International Journal of Psychiatry in Clinical Practice, 2005
Background. In spite of widespread recognition of the importance of maintenance treatment for bip... more Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.
Journal of Cerebral Blood Flow & Metabolism, 1987
The objective of this study was to evaluate simultaneous31P/1H nuclear magnetic resonance (NMR) s... more The objective of this study was to evaluate simultaneous31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (Pao220 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO220 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 μmol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metab...
OBJECTIVES Our primary aim was to describe unique correlates of functioning in bipolar disorder (... more OBJECTIVES Our primary aim was to describe unique correlates of functioning in bipolar disorder (BD). EXPERIMENTAL DESIGN The study included the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Patients were 41.9 +/- 12.7 years old, and diagnosed with bipolar I, II or NOS, verified by structured interview. Overall functionality was determined by the Range of Impaired Function Tool (LIFE-RIFT). Stepwise multiple regression analysis tested the non-redundant-independent-association of 28 variables on functioning. PRINCIPAL OBSERVATIONS Severity of depression symptoms was significantly and uniquely correlated with impaired functioning in the context of a wide variety of demographic and clinical variables, contributing 60.9% to the total variance in overall functioning (ss = 0.254, p = 0.0001). Substantial variance in function remains unexplained. CONCLUSIONS Intensity of depressive symptoms is the major determinant of impaired f...
Biological Psychiatry, 1991
Measurements of the lithium concentration in the occipital pole of the head and calf muscle of ni... more Measurements of the lithium concentration in the occipital pole of the head and calf muscle of nine patients with bipolar disorder in remission were performed using in vivo lithium-7 nuclear magnetic resonance spectroscopy (7Li NMR). 7Li NMR measurements were performed on a 1-m-bore, 1.85-T, superconducting magnet supplemented with a multinuclear spectrometer, using l l.5-cm-diameter surface coils. The average lithium concentration in the occipital pole was 0.36 +_ 0.10 mEq/L, whereas in the muscle it was 0.50 +__ O. 17 mEqlL, both lower than the average serum lithium concentration (0.79 +_ 0.23 mEqlL). The average brain/serum lithium concentration ratio was 0.47 +_ 0.12 whereas the average muscle~serum lithium concentration ratio was 0.66 +_ 0.20. There was a positive correlation between the brain versus serum and brain versus muscle lithium concentrations. The hypothesis is advanced that the minimal effective concentration of brain lithium concentration for maintenance treatment of bipolar disorder is around 0.2-0.3 mEq/L.
Journal of Affective Disorders, 2001
Background: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the cour... more Background: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the course of illness in otherwise refractory affective disorders. This collaborative study investigates whether T4 augmentation for a minimum of 12 months decreases bone mineral density (BMD) in 26 pre-and post-menopausal women with affective disorder. Methods: We measured BMD at the femoral neck, Ward's triangle, trochanter and lumbar vertebrae (L1-L4) in 13 premenopausal and 13 2 postmenopausal women with affective disorder using dual energy X-ray absorptiometry. BMD was expressed as g / cm and as a Z-score, calculated using bone density data from the international reference population standard. Results: The Z-scores for the pre-and post-menopausal women were within the reference range of the age and sex matched population standard. BMD for the composite group also did not differ either from the population standard. BMD in the lumbar spine and hip did not differ significantly between the pre-and post-menopausal groups. However, there were a relatively high number of postmenopausal patients with BMDs one S.D. lower than the population standard. Limitations: This is a cross-sectional study with a relatively small sample size. Conclusions: The study demonstrates that T4 augmentation treatment does not reduce BMD to a clinically significant degree in many women with affective disorder. However, the resilience of bone structure to T4 treatment may vary with site and menopausal status. This study underscores the need for regular assessment of BMD during adjunctive thyroid treatments for affective disorder, especially in postmenopausal women.
Biological Psychiatry, 1997
The regional distribution of 1-123 iofetamine (IMP) in the brain of 12 patients with rapid cyclin... more The regional distribution of 1-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 rain after injection of 3-4 mCi ofi-123 labeled lMP. The 1-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal lobe dysfunction in bipolar disorder.
Journal of Psychiatric Research, 2005
While the prevalence of bipolar disorder I is similar between men and women, the clinical course ... more While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes. Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women. The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle. The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.
International Journal of Psychiatry in Clinical Practice, 2005
Background. In spite of widespread recognition of the importance of maintenance treatment for bip... more Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.
Psychiatry Research, 2005
This prospective, longitudinal study investigated the frequency and pattern of mood changes betwe... more This prospective, longitudinal study investigated the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. Eighty patients with bipolar disorder selfreported mood and psychiatric medications daily for 3 months using a computerized system (ChronoRecord) and returned 8662 days of data. Of the total group of 80 patients, 47 took antidepressants; 33 did not. Patients taking antidepressants reported depression twice as frequently (29% of days vs. 13.8% of days). In both groups, two-thirds of all mood changes over a 1-, 2-and 3day period were small, between À5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (N10 on a 100-point scale) or in switches between depression and mania (0.7% if not taking antidepressants vs. 0.9% if taking), independent of diagnosis of bipolar I or II. Eighty-nine percent of patients taking antidepressants were also taking mood stabilizers. In this naturalistic setting, no significant difference between the rate of switches to mania or rapid cycling was found between those taking and not taking antidepressants, regardless of diagnosis. The primary difference in pattern between the groups was the time spent in depressed or normal mood, with minor daily mood variations.
Bipolar Disorders, 2010
Young RC, Schulberg HC, Gildengers AG, Sajatovic M, Mulsant BH, Gyulai L, Beyer J, Marangell L, K... more Young RC, Schulberg HC, Gildengers AG, Sajatovic M, Mulsant BH, Gyulai L, Beyer J, Marangell L, Kunik M, Ten Have T, Bruce ML, Gur R, Marino P, Evans JD, Reynolds CF III, Alexopoulos GS. Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD. Bipolar Disord 2010: 12: 56–67. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S.Aim: This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients.Method: There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions.Results: Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria.Conclusions: A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.
Acta Psychiatrica Scandinavica, 2006
Objective: To investigate seasonal and regional effects on bipolar I and II patients.Method: Th... more Objective: To investigate seasonal and regional effects on bipolar I and II patients.Method: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region.Results: A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients.Conclusion: The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.
Biological Psychiatry, 2003
Background: There is debate whether patients with rapid-cycling bipolar disorder (BD) are predisp... more Background: There is debate whether patients with rapid-cycling bipolar disorder (BD) are predisposed to thyroid axis abnormalities and whether this may contribute to development of rapid mood shifts. Using lithium carbonate as a challenge to the hypothalamic-pituitary-thyroid (HPT) system, we determined whether patients with rapidcycling BD are sensitive to the "antithyroid" properties of lithium. Methods: We studied the response to thyrotropin-releasing hormone (TRH) of HPT system hormones in 20 medication-free patients with rapid-cycling BD and compared these measurements with those of 20 healthy ageand gender-matched control subjects. The same measurements were repeated after both groups had received lithium carbonate for 4 weeks in sufficient doses to maintain blood levels between .7-1.2 mEq/L. Results: At baseline, the results of thyroid function tests, including the TRH challenge test, did not differ between patients and control subjects. After treatment with lithium, serum concentrations of thyroxine significantly decreased, whereas basal thyrotropin (TSH) and ⌬TSH max significantly increased in both patients and control subjects; however, patients had significantly higher ⌬TSH max after TRH stimulation. More patients than control subjects developed laboratory evidence consistent with grade III hypothyroidism after lithium treatment. Conclusions: Rapid-cycling BD is associated with a latent hypofunction of the HPT system. This dysfunction becomes manifest with short-term lithium challenge. Biol Psychiatry 2003;53:899 -905
Archives of General Psychiatry, 2000
Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effec... more Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.
Biological Psychiatry, 1997
To describe the relationship between mood and body weight, we analyzed 122 consecutive days of da... more To describe the relationship between mood and body weight, we analyzed 122 consecutive days of data from a 52-year-old woman with rapid cycling bipolar disorder, type II. The patient completed a daily log of selfreported mood, and weighed and recorded her weight daily. Mood and body weight were highly correlated (r = 0.60), and a decrease in mood preceded a decline in body weight by 3 days. Reports of loss of appetite on the Hamilton Depression Rating Scale also corresponded to periods of weight loss. There was a negligible difference in the patient's resting metabolic rate between a period of depression (1628 kcal/day) and of euthymia (1724 kcal/day). The association between depression and weight loss was primarily mediated by decreased food intake. Such patients should provide an excellent opportunity to study the regulation of body weight with affective illness.
American Journal of Geriatric Psychiatry, 2005
The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains u... more The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains understudied. Authors retrospectively examined response to lamotrigine, lithium, and placebo in older (>or=age 55) adults with Bipolar I disorder (DSM-IV) who participated in two mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. In all, 588 patients received double-blind lamotrigine (LTG, 100 mg-400 mg/day), lithium (Li, 0.8 mEq/L-1.1 mEq/L), or placebo (PBO); data from 98 older adults (LTG: 33, Li: 34, PBO: 31) were examined. Mean modal total daily doses were LTG 240 mg and Li 750 mg. LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. Lamotrigine and lithium may be effective and well-tolerated maintenance therapies for older adults with Bipolar I depression.
Neuropsychopharmacology, 2003
Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recen... more Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.
Archives of General Psychiatry, 2007
Context: Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipola... more Context: Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
American Journal of Psychiatry, 2008
In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of ... more In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.
International Journal of Psychiatry in Clinical Practice, 2005
Background. In spite of widespread recognition of the importance of maintenance treatment for bip... more Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.