Depression: Whybrow PC

Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, Möller HJ, Anonymous00106. · University Hospital Carl Gustav Carus, Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany. · World J Biol Psychiatry. · Pubmed #17455102 No free full text.

Abstract: These practical guidelines for the biological treatment of unipolar depressive disorders in primary care settings were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). They embody the results of a systematic review of all available clinical and scientific evidence pertaining to the treatment of unipolar depressive disorders and offer practical recommendations for general practitioners encountering patients with these conditions. The guidelines cover disease definition, classification, epidemiology and course of unipolar depressive disorders, and the principles of management in the acute, continuation and maintenance phase. They deal primarily with biological treatment (including antidepressants, other psychopharmacological and hormonal medications, electroconvulsive therapy, light therapy).

Bauer M, Whybrow PC, Angst J, Versiani M, Möller HJ, Anonymous00267. · University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA. · World J Biol Psychiatry. · Pubmed #12479080 No free full text.

Abstract: These practice guidelines for the biological treatment of unipolar depressive disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of the complete spectrum of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating patients with these conditions. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for depressive disorders, as well as from meta-analyses and reviews on the efficacy of antidepressant medications and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and was then categorized into four levels of evidence (A-D). The first part of these WFSBP guidelines on unipolar depressive disorders covered the acute and continuation treatment of major depressive disorder (Bauer et al 2002). This second part of the guidelines covers the management of the maintenance-phase treatment of major depressive disorder, as well as the treatment of chronic and subthreshold depressive disorders (dysthymic disorder, double depression, minor depressive disorder and recurrent brief depression). These guidelines are primarily concerned with the biological treatment (including antidepressants, lithium, other psychopharmacological and hormonal medications, and electroconvulsive therapy) of young adults and also, albeit to a lesser extent, children, adolescents and older adults.

Bauer M, Whybrow PC, Angst J, Versiani M, Möller HJ, Anonymous00268. · Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles (ULCA), 300 UCLA Medical Plaza, Suite 2330, Los Angeles, CA 90095, USA. · World J Biol Psychiatry. · Pubmed #12479086 No free full text.

Abstract: These practice guidelines for the biological treatment of unipolar depressive disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating patients with these conditions. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for depressive disorders, as well as from meta-analyses and reviews on the efficacy of antidepressant medications and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and was then categorized into four levels of evidence (A-D). This first part of the guidelines covers disease definition, classification, epidemiology and course of unipolar depressive disorders, as well as the management of the acute and continuation-phase treatment. These guidelines are primarily concerned with the biological treatment (including antidepressants, other psychopharmacological and hormonal medications, electroconvulsive therapy, light therapy, adjunctive and novel therapeutic strategies) of young adults and also, albeit to a lesser extent, children, adolescents and older adults.

Szuba MP, Amsterdam JD, Fernando AT, Gary KA, Whybrow PC, Winokur A. · Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, University Science Center, 3535 Market Street, Philadelphia, PA 19104, USA. · J Clin Psychopharmacol. · Pubmed #16012274 No free full text.

Abstract: BACKGROUND: Thyrotropin-releasing hormone (TRH) is a tripeptide that produces endocrine and behavioral effects in animals and humans. Some studies have shown transient antidepressant activity after morning administration of TRH. We hypothesized that nocturnal administration of TRH, when the circadian sensitivity of the TRH receptor is at its peak, may result in a more robust antidepressant effect. METHODS: Twenty patients with bipolar (BP) type I or BP type II major depressive episode (MDE) were given nocturnal intravenous TRH 500 microg (n = 10) or saline (n = 10) at midnight in a randomized, double-blind fashion. Antidepressant activity was assessed using the Hamilton Depression Rating (HAM-D), Young Mania Rating (YMR), and Profile of Mood (POMS) scales over a 48-hour period. Thyrotropin (TSH), total T4, and free T3 concentrations were measured before and after TRH administration. Data were analyzed using chi test, Fisher exact test, and repeated-measures ANOVA. RESULTS: Sixty percent of the TRH group and 10% of the saline group showed a > or =50% reduction in baseline total HAM-D score within 24 hours (P = 0.03). HAM-D ratings fell by an average of 52% after TRH administration versus 12% after saline administration (P = 0.038). There was a modest increase in YMR scores after TRH compared with saline (P < 0.032). No manic or hypomanic episodes were observed. Antidepressant effects of TRH lasted up to 48 hours. There was no correlation between DeltaTSH, DeltaT4, or DeltaT3 measures after TRH (or saline) administration and the change in HAM-D scores. CONCLUSIONS: Nocturnal TRH administration may produce a rapid antidepressant effect in some patients with BP I and BP II MDE.

Bauer M, London ED, Rasgon N, Berman SM, Frye MA, Altshuler LL, Mandelkern MA, Bramen J, Voytek B, Woods R, Mazziotta JC, Whybrow PC. · Neuropsychiatric Institute & Hospital, University of California Los Angeles , CA, USA. · Mol Psychiatry. · Pubmed #15724143 No free full text.

Abstract: Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Bauer M, Glenn T, Grof P, Rasgon NL, Marsh W, Sagduyu K, Alda M, Murray G, Quiroz D, Malliaris Y, Sasse J, Pilhatsch M, Whybrow PC. · Department of Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Germany Fetscherstr. 74, 01307 Dresden, Germany. · J Affect Disord. · Pubmed #19091424 No free full text.

Abstract: OBJECTIVE: Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood. METHOD: 360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month. RESULTS: No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month. CONCLUSION: Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

Bauer M, Glenn T, Grof P, Rasgon NL, Marsh W, Sagduyu K, Alda M, Lewitzka U, Sasse J, Kozuch-Krolik E, Whybrow PC. · Dept. of Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. · Soc Psychiatry Psychiatr Epidemiol. · Pubmed #19011720 No free full text.

Abstract: OBJECTIVE: This study investigated the frequency of episodes and subsyndromal symptoms based on employment status in patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 281) provided daily self-reported mood ratings for 5 months, returning 46,292 days of data. Data were analyzed using three employment status groups: disabled (n = 75), full-time employee or full-time student (n = 135), and other (n = 71). Demographic characteristics were compared by employment status. A univariate general linear model with employment status and other demographic variables as fixed factors and covariates was used to analyze the percent of days in episodes and percent of days with subsyndromal symptoms. RESULTS: While there was no significant difference in the percent of days in episodes among the employment groups, disabled patients suffered subsyndromal symptoms of depression twice as frequently as those in the full-time group. Disabled patients spent 15% more days either in episodes or with subsyndromal symptoms than those in the full-time group, equivalent to about 45 extra sick days a year. CONCLUSION: Frequent subsyndromal symptoms, especially depressive, may preclude full-time responsibilities outside the home and contribute to disability in bipolar disorder. Additional treatments to reduce the frequency of subsyndromal symptoms are needed.

Bauer M, Wilson T, Neuhaus K, Sasse J, Pfennig A, Lewitzka U, Grof P, Glenn T, Rasgon N, Bschor T, Whybrow PC. · Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Psychiatry Res. · Pubmed #18423616 No free full text.

Abstract: With the widespread recognition of the value of active patient participation in their care, ChronoRecord software was developed to automate daily self-reporting by patients with bipolar disorder. A prior study demonstrated concurrent validity between self-ratings on ChronoRecord and clinician ratings on the Hamilton Depression Rating Scale (HAMD), but validity with the Young Mania Rating Scale (YMRS) could not be shown due to a lack of data when the outpatients were manic (Bauer et al., Bipolar Disorders 6, 67-74, 2004). This study expanded upon the prior validation study to include inpatients with mania. Self-reported mood ratings on ChronoRecord and clinician ratings on the YMRS were obtained on the same day from 27 inpatients (57 ratings); these data were also combined with the ratings from the 80 outpatients (total 107 patients, 340 ratings). Using Pearson correlation, the self-reported ratings on ChronoRecord were significantly correlated with the YMRS. The accuracy of ChronoRecord to discriminate hypomania and mania was high, as described by the area under the receiver operating characteristic curve. Post-hoc analysis of the level of agreement between ChronoRecord and YMRS ratings was excellent or good in all cases using the kappa statistic. These data demonstrate concurrent validity between ChronoRecord and YMRS.

Rasgon NL, Kenna HA, Wong ML, Whybrow PC, Bauer M. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, CA 94305-5723, USA. <> · Psychoneuroendocrinology. · Pubmed #17317022 No free full text.

Abstract: Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.

Bauer M, Glenn T, Grof P, Pfennig A, Rasgon NL, Marsh W, Munoz RA, Sagduyu K, Alda M, Quiroz D, Sasse J, Whybrow PC. · Department of Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Germany. · J Affect Disord. · Pubmed #17224186 No free full text.

Abstract: OBJECTIVE: Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes. METHOD: 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes. RESULTS: Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder. LIMITATIONS: Self-reported data, computer access required, relatively short study length, no control group. CONCLUSION: Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

Glenn T, Whybrow PC, Rasgon N, Grof P, Alda M, Baethge C, Bauer M. · ChronoRecord Association, Inc., Fullerton, CA 92834, USA. · Bipolar Disord. · Pubmed #17042880 No free full text.

Abstract: BACKGROUND: Approximate entropy (ApEn) measures regularity in time series data, while traditional linear statistics measure variability. Using self-reported mood data from patients with bipolar disorder, this preliminary study addressed whether ApEn could distinguish (i) the 60 days prior to the start of a manic or depressed episode from the 60 days prior to a month of euthymia, and (ii) the 60 days prior to a manic episode from the 60 days prior to a depressed episode. METHODS: Self-reported mood data from 49 outpatients with bipolar disorder receiving standard treatment were analysed. The data contained 27 episodes (12 manic and 15 depressed), and 43 periods of 1 month of euthymia. For the 60 days prior to episode or euthymia, the ApEn, linear statistics and the correlation between linear and non-linear measures were calculated. RESULTS: ApEn was significantly greater in the 60 days prior to a manic or depressive episode than the 60 days prior to a month of euthymia. The onset of an episode was associated with greater irregularity in mood. Variability was also significantly larger and correlated with ApEn. ApEn was significantly greater in the 60 days prior to a manic episode than in the 60 days prior to a depressed episode, whereas measures of variability were not significantly different. Mood in the 60 days prior to mania was more irregular than prior to depression. CONCLUSIONS: Non-linear measures may complement traditional linear measures in the analysis of longitudinal data in bipolar disorder. A larger study is indicated.

Bauer M, Rasgon N, Grof P, Glenn T, Lapp M, Marsh W, Munoz R, Suwalska A, Baethge C, Bschor T, Alda M, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Charité Mitte (CCM), Schumannstrasse 20/21, 10117 Berlin, Germany. · Eur Psychiatry. · Pubmed #16782312 No free full text.

Abstract: This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

Bauer M, Grof P, Rasgon N, Bschor T, Glenn T, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charité--University Medicine Berlin, Campus Charité Mitte (CCM), Berlin, Germany. · Bipolar Disord. · Pubmed #16542186 No free full text.

Abstract: BACKGROUND: Early recognition of the prodromal symptoms of bipolar disorder, combined with a patient action plan, may help to prevent relapses. Sleep disturbances are frequent warning signs of both mania and depression. This study used cross correlation analysis to characterize the relationship between mood, sleep and bedrest in longitudinal data. METHODS: Self-reported mood, sleep and bedrest (mean 169 +/- 59 days of data per patient) from 59 outpatients with bipolar disorder receiving standard treatment were analyzed. The cross correlation function was used to determine the latency between the changes in sleep and/or bedrest and mood for time shifts of between -7 and 7 days. RESULTS: For sleep and/or bedrest, a significant inverse correlation was found with the change in mood, most commonly with a time latency of one day. Sleep plus bedrest had the strongest relationship with a change in mood, with a significant correlation in 24 of 59 patients (41%) for the night before or night of a mood change. The patients with a significant cross-correlation between mood and sleep plus bedrest reported about two thirds of all large sleep changes of >3 h and three fourths of all large mood changes (>20 on 100-unit scale). Patients with a significant cross correlation were more likely to take benzodiazepines. CONCLUSION: In most patients with a significant cross correlation between sleep and/or bedrest and mood, the mood change occurred on the day following the change in sleep and/or bedrest. Sleep changes from a previous pattern, especially those of more than 3 h, may indicate that a large mood change is imminent.

Bauer M, Rasgon N, Grof P, Gyulai L, Glenn T, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charite-University Medicine Berlin, Campus Charite-Mitte, Germany. · MedGenMed. · Pubmed #16369247 links to  free full text

Abstract: CONTEXT: Automating data collection from patients can improve data quality, enhance compliance, and decrease costs in longitudinal studies. About half of all households in industrialized countries now have a home computer. OBJECTIVE: While we previously validated the ChronoRecord software for self-reporting mood on a home computer with patients who have bipolar disorder, this study further investigates whether this technology created a bias in the collected data. METHODS: During the validation study, 80 of 96 (83%) patients returned 8662 days of data (mean, 114.7 +/- 32.3 SD days). The patients' demographics were compared with those of similar longitudinal studies in which patients used paper-based data collection tools. In addition, because demographic characteristics may influence attitudes toward technology, observer-rated scores on the Hamilton Depression Rating Scale and Young Mania Rating Scale were used to group patients by severity of illness, and the self-reported mood ratings were analyzed for evidence of bias from the patients' gender, ethnicity, diagnosis, age, disability status, or years of education. Analysis was performed using the 2-way analysis of variance and general linear model. RESULTS: The patients' demographic characteristics were very similar to those of patients with bipolar disorder who participated in comparable longitudinal studies using paper-based tools. After grouping the patients by severity of illness, none of the demographic variables had a significant effect on the patients' self-reported mood using the automated tool. CONCLUSION: The use of a computer does not seem to bias sample data. As with studies using paper-based elf-reporting, results from studies of patients using ChronoRecord software on a home computer to report mood can be generalized.

Bauer M, Rasgon N, Grof P, Altshuler L, Gyulai L, Lapp M, Glenn T, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Charité-Mitte, Schumannstr. 20/21, 10117 Berlin, Germany. · Psychiatry Res. · Pubmed #15698679 No free full text.

Abstract: 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 self-reported 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 3-day period were small, between -5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (>10 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.

Bauer M, Fairbanks L, Berghöfer A, Hierholzer J, Bschor T, Baethge C, Rasgon N, Sasse J, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Charité Mitte, Berlin, Germany. · J Affect Disord. · Pubmed #15555712 No free full text.

Abstract: BACKGROUND: This prospective study was designed to determine whether patients with prophylaxis-resistant affective disorders, receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), show evidence of accelerated bone loss compared to the reference population database. METHODS: In 21 patients, bone mineral density (BMD) of the spine (lumbar vertebrae L1-L4) and femur (femoral neck, trochanter, and Ward's triangle) was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy. RESULTS: There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD. LIMITATIONS: Relatively small sample size, no bone density assessment prior to treatment with L-T4, no patient control group with mood disorders who did not receive L-T4 treatment, and bone density follow-up intervals were variable. CONCLUSIONS: This study did not demonstrate evidence that long-term treatment of affectively ill patients with supraphysiological doses of L-T4 significantly accelerates loss of bone mineral density compared to the age-matched reference population. However, the decline of BMD in one individual patient underscores that caution is indicated and that regular assessment of BMD during longer-term supraphysiological thyroid hormone treatment is needed.

Rasgon N, Bauer M, Grof P, Gyulai L, Elman S, Glenn T, Whybrow PC. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2360, Palo Alto, CA 94305-5723, USA. · J Psychiatr Res. · Pubmed #15504425 No free full text.

Abstract: INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Bauer M, Grof P, Gyulai L, Rasgon N, Glenn T, Whybrow PC. · Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Berlin, Germany. · Bipolar Disord. · Pubmed #14996143 No free full text.

Abstract: OBJECTIVES: Longitudinal studies are an optimal approach to investigating the highly variable course and outcome associated with bipolar disorder, but are expensive and often have missing data. This study validates patient self-reported mood ratings using a home computer-based system (ChronoRecord) with clinician mood ratings on the Hamilton Depression Rating scale (HAMD) and Young Mania Rating scale (YMRS), and investigates the patient acceptance of the technology. METHODS: After brief training, outpatients with bipolar disorder were given the software version of an established paper based self-reporting form (ChronoSheet) to install on a home computer. Every day for 3 months, patients entered mood, medications, sleep, life events, and menstrual data. Weight was entered weekly. RESULTS: Eighty of 96 (83%) patients returned 8662 days of data. The mean days of data returned was 114.7 +/- 32.3 SD The mean percentage of days missing for mood data was 6.1% +/- 9.3 SD, equivalent to missing 7.3 day of the 114.7 days. Self-reported ratings were strongly correlated with clinician HAMD ratings (-0.683, p < 0.001). CONCLUSIONS: This study demonstrates concurrent validity between ChronoRecord and HAMD. Patients with bipolar disorder showed high acceptance of a computer-based system for self-reporting of daily data. Automation of data collection can reduce missing data and eliminate errors associated with data entry. This technology also enables on-going feedback for both patient and researcher during a long-term study.

Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC. · Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, USA. · Am J Psychiatry. · Pubmed #11578993 links to  free full text

Abstract: OBJECTIVE: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. METHOD: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. RESULTS: Six studies were identified. All were conducted with triiodothyronine (T(3)) and a tricyclic antidepressant. Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(3) in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention.

Gyulai L, Bauer M, Garcia-Espana F, Hierholzer J, Baumgartner A, Berghöfer A, Whybrow PC. · Department of Psychiatry, Bipolar Disorders Unit, University of Pennsylvania Medical Center, 3600 Market Street, Room 800, Philadelphia, PA 19104, USA. · J Affect Disord. · Pubmed #11578671 No free full text.

Abstract: 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 postmenopausal women with affective disorder using dual energy X-ray absorptiometry. BMD was expressed as g/cm(2) 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.

Hahn CG, Pawlyk AC, Whybrow PC, Gyulai L, Tejani-Butt SM. · Department of Psychiatry, University of Pennsylvania, Philadelphia 19104, USA. · Life Sci. · Pubmed #10350353 No free full text.

Abstract: Even though lithium has received wide attention in the treatment of manic depressive illness, the mechanisms underlying its mood stabilizing effects are not understood. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood stabilizing effects. Since lithium was recently reported to alter thyroid hormone metabolism in the rat brain, the present study investigated whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression. Adult male euthyroid rats were either given a diet containing 0.25% lithium or one without lithium for 14 days. Rats were sacrificed in the evening and RNA was isolated from different brain regions to quantitate the isoform specific mRNAs of THRs. Following 14 days of lithium treatment, THR alpha1 mRNA levels were increased in the cortex and decreased in hypothalamus; THR alpha2 mRNA levels were increased in the cortex and THR beta mRNA levels were decreased in the hypothalamus. No significant difference in the expression of these THR isoforms was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment appeared to regulate THR gene expression in a subtype and region specific manner in the rat brain. It remains to be determined whether the observed effects of lithium on THR gene expression are related to its therapeutic efficacy in the treatment of bipolar disorder.

Wirz-Justice A, Terman M, Oren DA, Goodwin FK, Kripke DF, Whybrow PC, Wisner KL, Wu JC, Lam RW, Berger M, Danilenko KV, Kasper S, Smeraldi E, Takahashi K, Thompson C, van den Hoofdakker RH. · No affiliation provided · Science. · Pubmed #14739440 No free full text.

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