Stanley Center for the Innovative Treatment of Bipolar Disorder

SECOND INTERNATIONAL CONFERENCE 
ON BIPOLAR DISORDER


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Table of Contents:

The Nature of Activity-Energy Among Unipolar Patients Who Switch To Bipolar and Those With a Stable Diagnosis

Authors: Hagop S. Akiskal, M.D., Jack D. Maser, Ph.D.
and Pamela Zeller, Ph.D.

Previous research (Akiskal et al., 1995) demonstrated four personality factors important to the switching process in Bipolar Disorder. One of these factors was Activity-Energy, with the unipolars who switched to Bipolar II Disorder showing significantly higher values on this factor than those unipolars who remained unipolar. Here we present data taken from the NIMH Collaborative Depression Study on 16 Bipolar I patients when depressed, 44 Bipolar II patients when depressed, and 460 unipolar patients who were never bipolar and remained unipolar over the five years of follow-up. Items on which the Bipolar II patients (now depressed) scored significantly (p < .05) higher than the other two groups were: 1) You are happiest when involved in some project that calls for rapid action, 2) You are often so much "on the go" that sooner or later you may wear yourself out, 3) You are able to work for unusually long hours without feeling tired, and 4) Others regard you as a lively individual. The data are interpreted to mean that Bipolar II patients, even when depressed, have elevated Activity-Energy compared to Bipolar I or unipolar patients.

The Altman Self-Rating Mania Scale (ASRM)

Authors: Edward Altman, Donald Hedeker, James L. Peterson, John M. Davis

Objective: We report on the development, reliability and validity of the Altman Self-Rating Mania Scale (ASRM).

Method: The ASRM was completed during medication washout and after treatment by 22 schizophrenic, 13 schizoaffective, 36 depressed, and 34 manic patients. The CARS-M and MRS were completed at the same time to measure concurrent validity. Test-retest reliability was assessed separately on 20 depressed and 10 manic patients who completed the ASRM twice during medication washout.

Results: Principal components analysis of ASRM items revealed three factors: mania, psychotic symptoms, and irritability. Baseline mania subscale scores were significantly higher for manic patients compared to all other diagnostic groups. Manic patients had significantly decreased post-treatment scores for all three subscales. ASRM mania subscale scores were significantly correlated with MRS total scores (r = 0.718) and CARS-M mania subscale scores (r = 0.766). Test-retest reliability for the ASRM was significant for all three subscales (r = 0.86, p<.001; r = 0.89, p<.001; r = 0.88, p<.001). Cronbach's alpha resulted in values of 0.79 for subscale 1 and 0.65 for subscales 2 and 3 respectively. Significant differences in severity levels were found for some symptoms between patient ratings on the ASRM and clinician ratings on the CARS-M. The presence or absence of insight was not significantly related to patients' responses on the ASRM. Mania subscale scores of greater than 5 on the ASRM resulted in values of 85.5% for sensitivity and 87.3% for specificity.

Conclusions: The ASRM is a brief, reliable, and valid self-rating scale for assessing the presence and/or severity of manic symptomatology. Advantages of the ASRM over other self-rating mania scales are discussed. Differences between patient and clinician ratings for some items (elevated mood, grandiosity) suggest some denial or under-reporting of severity levels in manic patients with mild to moderate symptomatology.

Increased Amygdala Volume on mri is Specific for bipolar Disorder

Authors: Altshuler LL, Bartzokis GB, Grieder T, Curran J, Mintz J

Brain MRI's (SPGR-3D acquisition in the coronal plane) were obtained on 12 bipolar, 14 schizophrenic and 18 control subjects to assess for differences in limbic system structures. 3-D volume reconstruction software (ISG Technologies) was used to reorient brain images in all three planes to decrease variance of head position across subjects. The hippocampus, parahippocampus, amygdala and temporal lobes were manually traced by a rater blinded to diagnosis. Limbic structures were delineated using internal brain landmarks. Data were analyzed using repeated measures factorial ANCOVA with age and height as covariates for temporal lobes, and age and temporal lobe as covariates for other limbic structures. Design factors of diagnosis, hemisphere and their interaction were included (general linear mixed model with unstructured covariates matrix). A significant main effect of diagnosis was seen (F2,40) = 5.2, p = .01. Pairwise contrasts revealed bipolar subjects had significantly larger amygdala compared to both schizophrenic (t = 3.2, df = 40, p = .003) and control (t = 2.1, df = 40, p = .04) subjects. No significant differences in temporal lobe volumes were found across groups and no significant interaction by hemisphere was observed. Course of illness variables (duration ill, number of manias, number of depressions) and their relationship to amygdala volume were assessed (general linear mixed model using data from both hemispheres, covaried for age, cortisol, and height). Illness variables were log-transformed as they were non-normally distributed. The number of episodes of mania, not total duration ill nor number of episodes of depressions, was significantly positively correlated with amygdala size (df = 19, F = 6.16, p = .02). Implications of these findings will be discussed.

Reduced Endogenous ADP-Ribosylation of G? s in Postmortem
Bipolar Disorder Brain

Authors: S. Andreopoulos, K.P. Siu, P.P. Li, and J.J.Warsh

Recent observations support altered signal transduction processes in bipolar disorder (BD). Findings of increased levels of the stimulatory guanine nucleotide (G) protein ? subunit, ? s, elevated forskolin-stimulated cAMP production, and alterations in cytosolic protein kinase A (a downstream target of cAMP action) in autopsied cerebral cortical regions from BD postmortem brain, support the notion that ? s-mediated hyperfunctionality occurs in this disorder. Lack of alterations in ? s mRNA levels, and negative evidence of linkage between the gene encoding ? s and BD, suggest hyperfunctional ? s may occur consequent to changes in posttranslational mechanisms governing ? s turnover, such as adenosine-diphosphate (ADP)-ribosylation. To test this hypothesis, endogenous and cholera toxin (CTX)-catalyzed ADP-ribosylation products of ? s were measured in postmortem temporal (n=9), occipital (n=10) and cerebellar cortex (n=7) of BD, and age and postmortem delay matched controls. ANOVA revealed significant main effects of diagnostic group (F=5.41, df=l ,51, p=0.025) and brain region (F=8.24, df=2,51, p=0.001) for endogenous ADP-ribosylation of ? s-s (short form of ? s). On posthoc analysis, endogenous ADP-ribosylated ? s-s was significantly lower (30%) in BD temporal cortex compared to controls (ROD = 0.62 ? 0.18, mean ? SD, vs 0.89 ? 0.26; t=2.55, df=16, p<0.05) but only showed a nonsignificant trend towards a decrement in occipital and cerebellar regions. Endogenously ADP-ribosylated ? s-L (long form) was only weakly detectable at the protein concentrations (250 ? g) used. CTX-catalyzed ADP-ribosylation of ? s-s was also somewhat, but not statistically significantly lower, in BD temporal cortex compared to controls. CTX-catalyzed ADP-ribosyled ? s-L was significantly higher (F=8.31, df=2,51, p=0.001) in temporal and occipital cortex compared with cerebellum but did not differ between groups (F=0.48, df=1,51, p=0.49). These preliminary observations suggest that disturbances in the mechanisms regulating ADP-ribosylation of ? s may occur in BD brain and raise the possibility that enhanced levels and hyperfunctionality of ? s may occur secondary to alterations in these processes .

Review of Data From a Newly Established Bipolar Unit at a University Hospital in Turkey

Authors: _ zerdem AyÕ egh l, M.D., Tunca Zeliha, M.D., Kaya Nezaket, M.D.

We report data from our bipolar outpatient unit collected by using life charts of 61 registered patients (45 hospitalized during last 5 years, 16 referred from the outpatient unit). Sex distribution: Female: 42, Male:19; F/M=2.2. Age range: 19-75, (mean: 38.3? 15.1). Status of employment: 36.1% housewife, 16.4% student, 14.8% professional, 8.2% retired, 8.1% unemployed, 14.7% other. Most of our patients had either university (41%) or high school level (26.2%) education. 62% came from inner town. 41% were married, 41% unmarried and only 6.6% were divorced for reasons other than bipolarity. 45 patients were bipolar I and 16 bipolar II. Age of onset: 27.3? 11.6 (range: 13-72). 6.8% of bipolar I and 37.5 % of bipolar II patients had multiple episodes which could not be counted reliably. Total number of documented episodes were 5.9? 5.1(1-28) and 7.0? 5.3 (3-21) for bipolar I and bipolar II, respectively. There was no correlation between the age of onset and number of episodes in both groups. Mean number of episodes before lithium treatment was 4.0? 3.2. Thirty-eight patients (63%) received neuroleptics at some time during the course of illness, mostly for the acute phase for 2-4 weeks, and 10 (16.4%) were given electroconvulsive therapy. Five patients (8.2%) received neuroleptics for 57.6? 44.2 months because of delayed diagnosis. Twenty-one of 34 patients (61.8%) received lithium alone, 11 (32.4%), a combination of lithium with carbamazepine and/or valproate, and two, valproate and carbamazepine alone. Mean duration of lithium treatment was 39.1? 42.6 months. Thirteen patients stopped lithium for various reasons and developed a new episode within a year. Clinical status of the 34 patients when last seen were euthymic (27), depressed (5), hypomanic (1) and manic (1). We would like to emphasize the importance of life chart in following and documenting bipolar patients.

Lithium Regulation of Brain MyoInositol in Bipolar Affective Disorder

Authors: Joseph M. Bebchuk, M.D., Gregory Moore, Ph.D.,
Husseini K. Manji, M.D.

The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with Bipolar Affective Disorder. Lithium continues to be the mainstay of treatment for both the acute and prophylactic treatment of Bipolar Affective Disorder. However, despite its unquestioned efficacy, the biochemical basis for lithium's mood-stabilizing actions remains to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy. Studies such as these indicate two important and highly clinically relevant directions for future research: firstly, the need to better identify patients likely to respond to lithium treatment, and secondly, the necessity to develop more effective treatment regimens.

The most widely accepted hypothesis underlying lithium' s therapeutic efficacy is the inositol depletion hypothesis. This hypothesis posits that lithium produces a relative depletion of myoinositol in critical areas of the brain and it is this depletion of a major precursor of the phosphoinositide second messenger system which results in its therapeutic effects. Despite the attractiveness of the inositol depletion hypothesis, it has never been investigated in manic-depressive patients. Thus, there is a clear need to determine if lithium reduces the levels of myoinositol in critical brain regions of individuals with manic-depressive illness, and if individual differences in susceptibility to lithium-induced CNS myoinositol reductions represent major factors determining resistance or sensitivity to lithium's therapeutic effects.

We are therefore conducting resistance or sensitivity to lithium's spectroscopy (MRS) to measure levels of myo-inositol (proton spectroscopy) and inositol-1-phosphate (phosphorus spectroscopy) in the following brain areas of manic patients and healthy volunteers: i) frontal cortex; ii) hippocampus; iii) occipital cortex; iv) cerebellum. Myoinositol and inositol-l-phosphate levels are being examined at 3 times points: i) at baseline; ii) after acute (5-7 days) lithium administration; and iii) after chronic (4 week) lithium administration. To date, we have found that similar to the effects observed in rodent brain, lithium reduces the myoinositol levels in critical brain regions in patients suffering from Bipolar Affective Disorder. The hypothesis that lithium-induced alterations in brain myoinositol levels are associated with responsiveness to its therapeutic effects are currently under investigation.

ADHD and Bipolar Disorder as Predictors of Clinical Response to Lamotrigine

Author: Jeffrey L. Berlant, M.D., Ph.D.

Objective: The presenter explored predictors of clinical outcome associated with treatment of severe mood disorders with lamotrigine.

Method: Fourteen adults with unsatisfactory response to conventional medication treatment of severe mood disorders received lamotrigine in a naturalistic trial. Outcome variables included lamotrigine discontinuation and retrospective Clinical Global Impression scores for six variables: overall outcome, depression, hyperactivity, concentration, mood lability, and general functioning. The investigation examined associations of lamotrigine effects with age, sex, mood disorder diagnosis, ADHD diagnosis, and Wender Utah Rating Scale score.

Results: Ten patients met DSM IV criteria for Bipolar Disorder, ten for ADHD, and seven (50%) for both. Mean group WURS score was 41.6, mean age 37.1 years, with a 1:1 sex ratio. Mean duration of treatment was 16.9 weeks, with 57% of cases discontinuing lamotrigine. Mean CGI scores for the six variables suggested mild improvement. Age and sex had no significant effect on any outcome variables. WURS score significantly predicted medication continuation (mean 52 versus 34 for discontinuers), and five CGI scores correlated with the WURS (r = 0.50 to 0.62). Diagnosis of Bipolar Disorder had no significant effect on discontinuation rates or CGI scores, although all four non-bipolar patients discontinued lamotrigine use. Four CGI scores were significantly higher for those with ADHD diagnoses (overall outcome, depression, hyperactivity, and functioning). The lowest discontinuation rates and highest CGI outcomes were for the group with both Bipolar Disorder and ADHD. WURS scores were mildly correlated with five CGI outcomes for bipolar cases (r = 0.59 to 0.73). For five CGI outcomes the most robust correlation with WURS scores occurred with ADHD diagnosis (r = 0.70 to 0.85), and no further predictive power appeared when bipolar and ADHD groups were combined.

Conclusions: Lamotrigine may improve Bipolar Disorder. Elevated WURS scores and ADHD diagnosis may further predict treatment response. Further studies are definitely warranted.

Case Report of Synergistic Response of Rapid Cycling Bipolar Disorder to
Lamotrigine, Risperidone, and Verapamil

Author: Jeffrey L. Berlant, M.D., Ph.D.

Objective: The poster presents several months of daily mood chart recordings from a patient with bipolar disorder to demonstrate the effect of a series of medication combinations on cycle frequency.

Method: A professional male, now 33, with Bipolar Disorder, Mixed Type, Rapid Cycling Subtype, and Attention Deficit Hyperactivity Disorder, kept daily mood chart recordings for 14 days in February 1995 and thereafter from July 1995 until December 1996, except for an eight-week hiatus in early 1996. Using a 10 point scale (presented on the poster), he operationalized his mood states to facilitate internal reliability of scoring. He also developed methods for recording diurnal mood lability as an outcome variable. Records of changes in medication and dosage associate therapeutic changes with control of mood cycling frequency and diurnal lability.

Results: Following unsatisfactory trials of valproate and verapamil, carbamazepine and levothyroxine diminished mood cycling and lability but left a chronically depressed state. Decreased carbamazepine lifted mood level but released mood cycling. A verapamil/carbamazepine trial reduced mixed state symptoms and decreased mood reactivity but left significant residual depressed mood. An empirical trial of B12 injections was unhelpful. When mood cycling and chronic depression worsened, addition of risperidone in low doses mildly improved mood level and cycling. Trial discontinuation of verapamil resulted in a major depressive dip, with recovery within a day after reinstitution of verapamil. Beginning in April 1996, a combination trial of lamotrigine, verapamil, and risperidone elicited general mood enhancement, but decreasing the dose of risperidone released mood cycling and increased mood lability. The patient is currently doing well on lamotrigine 250 mg/d, verapamil 320 mg/d, and risperidone 1 mg/d.

Conclusions: Combination psychopharmacotherapy may be essential for some rapid cycling patients. Lamotrigine, but only in combination with other mood stabilizing agents, was beneficial for this individual.

Diagnostic Criteria for Mixed Manic States

Authors: Frederick Cassidy, M.D., Eileen Ahearn, M.D., Ph.D.,
Elizabeth Murry, Kara Forest, M.D.
and Bernard J. Carroll, M.B., Ph.D.

Although mixed states of bipolar disorder have been long recognized, no consensus of how best to define them has developed. Numerous researchers have suggested that the definitions adopted by DSM-III-R and DSM-IV are too rigid. Two hundred thirty-seven subjects meeting criteria for Bipolar Disorder, manic or mixed, were evaluated both by DSM-III-R criteria and the Scale for Manic States. In a previous factor analysis of this scale, a factor was identified which represented dysphoric mood in manic patients. The distribution of subject scores on that factor was bimodal, with one mode comprising patients with high scores for dysphoric mood, guilt, lability, anxiety, and suicidality.

That distribution was used to divide the cohort into two groups. Sensitivities, specificities, positive and negative predictive values and diagnostic efficiencies for the dysphoric mode of that factor were calculated for various signs and symptoms suggested to be relevant to mixed states. Six symptoms: depressed mood, anhedonia, fatigue, feelings of guilt or worthlessness, recurrent thoughts of death or recurrent suicidal thoughts, and anxiety had adequate positive predictive values for inclusion in a definition of mixed states. Various definitions of mixed states were tested against this empirical subgroup of dysphoric mania, and receiver operating curves were constructed for these definitions. A definition comprising all six symptoms performed better than the DSM-III-R definition for Bipolar Disorder, mixed. These data suggest that DSM-III-R criteria for Bipolar Disorder, mixed, are too rigid. Alternate definitions of mixed states are less restrictive and provide a better compromise between sensitivity and specificity. Further studies are needed to test the validity of current definitions of mixed bipolar disorder.

Neurometabolic and Neuropsychologic Functioning in Bipolar Children Pre- and Post- ECT

Authors: H.E. Courvoisie, M.D, S.R. Hooper, Ph.D., L. Kwock, M.D.

Electroconvulsive Therapy (ECT) is a well-established treatment for depression. Although reported effective in depressed children as young as five years old, questions remain about the developmental impact of ECT in children. To date, there are no systematic reviews of treatment impact on neurometabolic and neuropsychological outcome in children.

This presentation describes three prepubescent male children who received ECT, for a primary BPAD with intractable mania. Each had failed multiple courses of mono- and polytherapy of mood stabilizers, and other appropriate medications.

Subjects were recruited into this study as part of a larger study examining children with BPAD. The parent/caregiver participated in a structured interview, and the mania rating scale was completed by designated staff. All subjects underwent a drug washout prior to ECT. BPAD probands received a comprehensive neuropsychological evaluation and Magnetic Resonance Spectroscopy (MRS). The MRS targeted the neurometabolic activity in bilateral frontal regions based on preliminary hypotheses from our ongoing BPAD study. Two subjects received 6-12 unilateral (left-sided) treatments. One child started with unilateral and then had bilateral. All policies formulated by the American Psychiatric Association for ECT were followed.

Two bipolar patients underwent single volume localized proton MRS emphasizing the frontal brain region. Post-ECT, a 2-4 fold increase in the lipid/lactate peak area resonances was found in comparison with the pre-ECT MRS study. No significant changes were found in peak areas for N-acetylaspartate, choline, creatine, and myoinositol. These findings correlate with proton MRS studies performed by Woods and Chiu (Ann. Neuol. 1990; 28:745-749) on ECT-treated adult patients.

Concurrent neuropsychological testing revealed average intellectual abilities but significant interprofile variability in all three patients. Short-term memory impairments were noted in two patients. Follow-up MRS and neuropsychological testing will be conducted six months post-treatment.

Bipolar Disorder as Manifested Within Borderline Personality Disorder

Authors: Deltito JA, Martin LY, Riefkohl J, Kissilenko A, Halligan P,
Austria B, Morse C, Corless P

Several lines of evidence suggest that many patients classified by DSM-IV as suffering from Borderline Personality Disorder may fundamentally suffer from a Bipolar Spectrum Disorder. These findings may also extend to other Axis II Disorders marked by affective instability such as Histrionic and Sociopathic Personality Disorders. Evidence further suggests family members of patients with Borderline Personality oftentimes suffer from psychiatric syndromes which present with increased irritability and affective instability. In addition, preliminary investigation suggests that medications used to control Bipolar Disorder, such as Divalproex Sodium may be quite helpful in the overall treatment of borderline patients.

Noting the above-mentioned factors, we have embarked on a psychopathologic study of the Borderline Personality Disorder Syndrome with the intent to document and analyze the contribution of bipolar spectrum pathology to the patients’ overall psychopathological syndromes.

Data collection is now half completed and should be concluded by the early Spring of 1997. Through the use of a modified version of the SCID, the Cornell Personality Organization Questionnaire, the Family History-Research Diagnostic Criteria (FHRDC) and other tools, we have attempted to quantify the contribution of Bipolarity to the borderline state. Preliminary analysis of the data demonstrated this contribution to be significant. Through the use of logistic regression models we plan to make some determination regarding whether bipolar disorder should be conceptualized as a frequently encountered co-morbid entity, part of a larger syndrome with Borderline Personality Disorder or truly part of its causality.

This psychopathological study is meant to inform decisions regarding the use of psychopharmacological treatment regimens in the treatment of Borderline Personality Disorder and is a precursor to a larger controlled clinical trial of such agents.

The Usefulness of Divalproex Sodium in the Treatment of Bipolar and Behavioral Disorders on an Adolescent Inpatient Unit

Authors: Deltito J, Levitan J, Damore J, Zambenedetti M, Hajal F

Controlled clinical trials provide necessary information regarding the safety, tolerability and efficacy of any psychopharmacologic agent. Yet constraints inherent in such methodology leave many issues related to the usefulness of these preparations in the naturalistic setting unanswered. Therefore, in order to receive a full picture of a given agent's usefulness, data from controlled clinical trials needs to be complemented with data from the naturalistic setting.

With this in mind, we have completed the data collection relevant to the use of Divalproex Sodium in all patients admitted to an adolescent inpatient unit of New York Hospital-Cornell Medical Center-Westchester Division over a one-year period. In all, data was collected on 200 patients, 30 percent of whom were treated with Divalproex Sodium.

Data collection is completed but is in the process of analysis.

Preliminary analysis would suggest Divalproex Sodium to be a useful (safe, well-tolerated, and effective) medicine to use in this patient population for treating bipolar spectrum disorders and other commonly encountered behavioral disturbances in adolescents.

Prophylactic efficacy of lithium, carbamazepine, valproate and their combination in bipolar disorder

Authors: Kirk D. Denicoff, M.D., Earlian Smith-Jackson, R.N.,
Ann L. Bryan, B.A., S. Omar Ali, B.S., and Robert M. Post, M.D.

Objective: To study the prophylactic efficacy of lithium, carbamazepine, valproate and their combination in bipolar illness.

Method: Fifty-two outpatients who met DSM III-R criteria for bipolar illness (29 BPI, 23 BPII) were randomized in a double-blind design for an intended one year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and a third year on the combination. Antidepressants and antimanic agents were used acutely as necessary. Patients entered a fourth phase of valproate (? ) lithium because of inadequate response and/or significant side effects; inadequate responders were offered triple mood stabilizer therapy (lithium, valproate, and carbamazepine). Patients received detailed evaluations monthly, and daily life chart ratings of the degree of functional incapacity associated with mania or depression.

Results: Evaluable patients who had marked or moderate improvement on the Clinical Global Impressions (CGI) scale for each phase were: lithium 14 of 42 (33.3%); carbamazepine 11 of 35 (31.4%); lithium + carbamazepine 16 of 29 (55.2%); valproate (? ) lithium 6 of 18 (33.3%); and triple therapy 3 of 7 (42.9%). The cumulative response rate was only 61.9% (19.0% marked,42.9% moderate in any phase) from the original randomized evaluable cohort. At baseline year (worst year of retrospective illness) patients were manic 26.0% of the year and depressed 33.0% of the year; this improved to 5% and 16% respectively during the patients' best treatment phase. Thus while 62% showed a noticeable improvement in at least one of the prospective phases, 38% did not, and substantial morbidity remained.

Conclusion: These data on the one hand highlight that persistence in sequentially trying and adding different mood stabilizing treatments can achieve good results for many bipolar patients. On the other hand, the lack of adequate response in a large proportion of our patients highlights the substantial need for new treatment options in the long-term prophylaxis of patients with bipolar illness.

Lamotrigine treatment in rapid cycling bipolar disorder (BPD): clinical and biological correlates

Authors: I.N. Ferrier, D. Potkins, D. Eccleston

Recent evidence suggests that the outcome in BPD is less good than previously thought with approximately 30% of patients showing an inadequate response to lithium. There are a variety of poor outcomes in BPD, one of which is rapid or ultra rapid short cycling. We compared 15 patients with BPD with poor outcome with an age sex matched population of BPD who had a good response to lithium. The degree of family history, age of onset and length of illness was similar between the two groups. The poor outcome group exhibited a greater frequency of sub-cortical patchy white matter lesions (PWML) on MRI and increased frequency of temporal lobe slow wave activity on the EEG.

The more severe forms of rapid cycling disorder respond to anticonvulsants, and in the more severe cases, combinations of anticonvulsants and lithium are required. Seven rapid cycling BPD patients (mean age 50) were put on lamotrigine in addition to lithium and sodium valproate or carbamazepine. The patients had been ill for a mean duration of 15 years and all had shown failure to respond to lithium with a partial response to anticonvulsants. Three of the patients did well over 2-3 years when lamotrigine was added in a dose of 150 to 200 mg, with a marked reduction in the frequency and severity of episodes. Two patients showed no change over one year (maximum dose was 100 mg). Two patients exhibited a worsening at the onset of the study with increased severity of over-valued ideas. Medication was discontinued immediately. All of the patients who showed a good response had an abnormal EEG before the introduction of lamotrigine but no correlation between response to medication and PWMLs has been found.

LONGITUDINAL ASSESSMENT OF THYROID FUNCTION AND MOOD STABILITY IN MANIC DEPRESSIVE ILLNESS

Authors: M.A. Frye, K.D. Denicoff, A. Bryan, E. Smith-Jackson, S. Omar Ali, D. Luckenbaugh, G.S. Leverich, and R.M. Post

There is an emerging consensus that a decrease within the normal range of thyroid indices occurs in association with an acute response to a number of antidepressant, mood stabilizing, and cognitive therapy treatments (Whybrow 1981, Joffe 1994, 1996). Longer term studies of thyroid indices, however, have shown a number of predictors of relative mood instability, including low T3 levels associated with relapse in bipolar patients maintained on lithium (Hatterer 1988, Baumgartner 1995) and increased incidence of concurrent panic disorder and relative antidepressant inefficacy with subclinical hypothyroidism (Joffe 1992). This study was conducted to evaluate the incidence of de novo hypothyroidism (grades I & II) and to assess whether these thyroid changes were associated with clinical response or mood instability.

52 bipolar outpatients participated in a randomized double blind study comparing efficacy of lithium, carbamazepine, and lithium/carbamazepine combination for up to 3 years of prospective evaluation (Denicoff 1996). Patients on thyroid supplementation prior to prospective study were not included in this analysis.

The incidence of de novo hypothyroidism grade I or II was 40 % (12/30) during lithium monotherapy, 0% during carbamazepine monotherapy, and 17.6% (3/17) for the lithium/carbamazepine combination. This group was 67% (8/12) women, 33% (4/12) men, 67% (8/12) rapid cyclers, and 33% (4/12) nonrapid cyclers. The time course to develop an elevated TSH was 76.6 days +/- 49.7 into lithium monotherapy (mean dose 1247.1 mg +/- 261.8) and 119.3 days +/- 56.3 into the combination (mean dose lithium 1178.6 mg +/- 103.5 and carbamazepine 614.3 mg +/- 186.4). Pearson correlation of elevated TSH with LCM, Hamilton, Young, and Spielberger ratings were not significant. There was no significant difference between responders and nonresponders based on subclinical hypothyroid state (Fisher's exact test: one tail p=0.53 for monotherapy, p=0.36 for combination).

Further data will be presented evaluating free T4, T3, and TSH with mood at monthly intervals over the course of prospective treatment. Preliminary analysis reveals a protective effect by carbamazepine for lithium induced subclinical hypothyroidism.

Comorbidity of Axis I Bipolar Disorder and Axis II Personality Disorder:
Prevalence and Clinical Determinants

Authors: Elizabeth L. George, M.A. and David J. Miklowitz, Ph.D.

Many studies have examined the prevalence and predictive validity of Axis II disorders among unipolar depressed patients, but few have examined these issues among bipolar patients. The few studies that do exist suggest that Axis II pathology does indeed complicate the diagnosis of bipolar disorder, but is not prevalent as frequently as one might expect.

We examined the prevalence of Axis II disorder in 47 bipolar patients who had achieved remission of symptoms, using the Personality Disorder Examination (PDE). We present data on the prevalence of personality disorders in this sample, as well as mean PDE dimensional scores. Finally, we offer preliminary findings on the associations between Axis II comorbidity and the prospective one-year course of bipolar disorder in the domains of social-occupational functioning and medication compliance. Initial findings suggest that Axis II disorders can be rated reliably among bipolar patients in remission.

Is Bipolar Disorder Underdiagnosed?Are Antidepressants Overutilized?

Authors: S. Nassir Ghaemi, M.D., Gary S. Sachs, M.D., Alice M. Chiou, Ananda K. Pandurangi, M.D., and Frederick K. Goodwin, M.D.

Objectives: Clinical experience suggests that bipolar disorder (BP) may be underdiagnosed, mood stabilizers may be underutilized, and antidepressants may be overutilized in BP. This study examined these hypotheses.

Methods: In one year, all patients in an affective disorders unit of a university hospital with discharge diagnoses of BP (n=50) or schizoaffective disorder (n=5, all manic type) were diagnosed prospectively by a psychiatrist with expertise in affective disorders based on a semistructured clinical interview using DSM-IV criteria. Clinical Global Impression of Improvement (CGI-I) scores were assigned retrospectively, blind to admission or discharge diagnoses.

Results: 21/50 (42%) of bipolar patients carried other diagnoses in the community, mainly unipolar disorder (UP) (n=19/21; 90.5%). The semi-structured clinical interview identified 50% (25/50) of BP patients with either no previous diagnosis or other diagnoses. 21 patients not diagnosed as bipolar before admission remained undiagnosed longer (7.9+8.8 years after first professional contact) than 25 who were diagnosed (0.88+8.8 years). On admission, only 1/3 used mood stabilizers, yet 1/3 used antidepressants. All except 2 (3 .7 % ) were tapered off antidepressants, with overall improvement upon discharge. Valproate was more frequently used than lithium. Response to valproate alone was lower (40%) than response to valproate plus lithium or other adjuncts (antipsychotic or clonazepam, 67-70%). With aggressive anticonvulsant treatment, response rates were similar (50-57%) for pure mania, mixed episodes, and rapid-cycling episodes. On admission, 8/10 with acute depression used antidepressants, and only 3 received mood-stabilizing cotherapy. At discharge, only 2 remained on antidepressants, and all received mood stabilizers, with mild to moderate improvement in 7/10.

Conclusion: Bipolar disorder (BP) is underdiagnosed. Systematic application of DSM-IV criteria identified 50% as previously misdiagnosed or undiagnosed. Mood stabilizers were underutilized and antidepressants overutilized. Good treatment response was achieved acutely with aggressive use of anticonvulsants, especially with lithium or adjuncts.

RELAPSE AND QUALITY OF LIFE IN BIPOLAR DISORDER

Authors: Joseph F. Goldberg, M.D. and Martin Harrow, Ph.D.

Chronic affective illness has been shown to impair overall quality of life (QOL) even after acute symptoms remit. Impaired role performance, and the economic, occupational and social disability caused by depression have been well-described; however less is known about the impact of bipolar illness on these areas. We assessed relapse,outcome, and key areas of QOL in bipolar and unipolar-depressed patients, followed up over an 8-year period. Components of QOL were examined in relation to affective relapse and objective measures of functional outcome.

A sample of 206 RDC-bipolar I and nonpsychotic unipolar-depressed inpatients from the Chicago Follow-up Study were interviewed at index and again after 2, 4.5 and 8 years. Affective relapse, rehospitalization, and global outcome were rated using standardized instruments. These factors were then compared with a 5-point QOL index based on patients' satisfaction with work, social life, economic status, living circumstances, and self-perceived overall mental health.

Results indicated that during each follow-up period, 20-30% of bipolar patients were dissatisfied with at least one aspect of QOL. Functional outcome measures, including nonrehospitalization and the percentage of time spent in occupational roles, were correlated with greater work and social satisfaction among unipolar patients, but not bipolar patients (p<.05). Affective relapse was strongly linked to work dissatisfaction among bipolar patients (p<.05), but not unipolar patients. In addition, over one-quarter of all patients who had no affective syndrome in the year preceding each follow-up still viewed their overall mental health as impaired.

Among unipolar depressed patients, QOL appears less related to affective relapse than to objective signs of role functioning and adjustment. In contrast, among bipolar patients, poor QOL appears closely tied to recurrent manic or depressive episodes, but is less clearly linked to disrupted work and social performance. Diminished QOL is a persistent feature for one-quarter or more of affectively disordered patients, even in the absence of a recent affective relapse.

Suicidality Predicts Nonremission From Acute Bipolar Episodes

Authors: Joseph F. Goldberg, M.D., Jessica L. Garno, B.S.,
Andrew C. Leon, Ph.D., and James H. Kocsis, M.D.

Suicidality is common in bipolar illness, yet little is known about the relative suicide risk for subtypes of bipolar patients. The relationship between suicide attempts and overall course of illness in mania is also poorly understood. Previous studies have identified comorbid substance abuse, inadequate treatment, rapid cycling, and psychosis as being associated with an increased risk for suicidal behavior in bipolar disorder. This pilot study examined the frequency and lethality of pre-index suicide attempts among a large cohort of bipolar patients hospitalized between 1991-1995. Previous suicidality was examined in relation to 1) subdiagnoses of "mixed" or "pure" mania; 2) overall severity of illness, and 3) likelihood for acute remission during hospitalization.

Records were reviewed for 182 DSM-III-R Bipolar I inpatients. The number, method, and outcome of previous suicide attempts were rated. Patients were classified as having mixed-dysphoric or pure-manic episodes along standardized guidelines. Demographic data were obtained from clinical records, along with information regarding current suicidality, affective and psychotic symptoms, rapid cycling, medication use, previous substance abuse and weekly clinical improvement rated by Clinical Global Impressions scores. Factors hypothesized to predict nonremission from the index episode were analyzed by logistic regression.

Results indicated: 1) prior suicide attempts were more common in patients admitted for mixed mania (35%) than pure mania (9%) (p<.05); 2) both prior and current suicidality were strongly correlated with the number of depressive symptoms among mixed-state bipolar patients (r =.23, p <.01); 3) the likelihood of acute remission was reduced by 66% for every suicide attempt made prior to index (OR=0.44, 95% CI=0.23 to 0.84).

The findings suggest that mixed-state bipolar patients have a higher suicide risk than pure- manic patients. Past suicidality may be a marker for both future mixed mania and recurrent suicidality. Mixed-manic patients may represent a subpopulation at higher risk for demoralization and suicide, as a result of increased unpredictability and chaos of internal mood states.

Adjunctive Cognitive-Behavioral Group Treatment for Bipolar Disorder

Authors: Robert A. Gould, Ph.D., Dina Hirshfeld, Ph.D.,
Noreen A. Reilly-Harrington, M.S., and Gary Sachs, M.D.

Bipolar disorder is costly in terms of psychiatric costs, medication costs, rehabilitation services, lost wages and productivity, and, in some cases, loss of life. Recent studies indicate that even patients who have good acute responses to medication and adequate maintenance treatment have a five-year relapse rate of 73%. Even after symptoms have resolved, social and functional impairment continue. Clearly, interventions which reduce the frequency and severity of episodes while improving patients' overall functioning are needed. Although numerous reports suggest that cognitive-behavioral therapy (CBT) may represent a promising adjunctive treatment, to date no controlled clinical trial of group CBT for bipolar disorder has been published.

We are conducting an ongoing controlled clinical trial comparing a cognitive-behavioral group treatment (CBGT) to standard pharmacotherapy (SPT) alone in reducing the frequency and severity of episodes, and social and occupational dysfunction over 3-month treatment and follow-up periods. Participants were evaluated at baseline via a structured clinical interview and self-report measures and were assessed monthly thereafter by an independent clinical interviewer blind to treatment condition. The CBGT is a 12-week manualized group treatment which targets: 1) medication compliance, 2) recognition of acute symptoms and personal triggers for episodes of mania and depression, 3) development of individualized plans for coping with symptoms, 4) cognitive-behavioral therapy for depression, and 5) improving stress management, conflict resolution and family functioning.

We will present preliminary data on this effectiveness of CBGT relative to SPT for approximately 20 patients who have undergone these interventions in our clinic during the past 7 months. Results will be discussed in terms of augmenting pharmacotherapy and mitigating the impact of this devastating disorder.

Clinical Subtypes of Soft Bipolar Disorders in a French
Multicenter Study: EPIDEP

Authors: Hantouche EG, Fraud JP, Allilaire JF, Sechter D, Akiskal HS

This paper presents the preliminary results of a French multi-center study in progress on 600 out and inpatients with major depressive episodes (EPIDEP). The aim of EPIDEP is to show the feasibility of validating new clinical bipolar subtypes such the spectrum of Soft Bipolar Disorders: BP type II (major depressives associated with Hypomania, Cyclothymia or Hyperthymia).

Methodology: It involves 1) training French psychiatrists in 25 sites; 2) construction of a protocol based on criteria of DSM-IV and Akiskal, as well as instruments modified from the work of Angst (Hypomania Checklist), Ahrean-Carroll (manic scales), HAM-D28 + Rosenthal (Depression scale), semistructrured interview for evaluation of affective temperaments (Akiskal et al), family history and comorbidity (Winokur's user's friendly criteria); 3) prospective follow-up (3 months).

Results: Preliminary results are presented on 250 patients with MDE. The global rate of Soft Bipolarity (BP-II disorder) was about 40%. By comparison to unipolar depressives, BP-II was significantly different on the following parameters: higher frequency of suicidal thoughts and hypersomnia during the current depressive episode; younger age of onset of first depression; higher rate of recurrence; higher scores on Hypomania checklist and Cyclothymia questionnaire; higher switching rate under current treatment by 35-40% (vs 5% in UP group) which was more correlated to level of Cyclothymia than to Hypomania score.

Clinical Subtypes of Acute Mania in a French Multicenter Study: EPIMAN

Authors: Bourgeois ML , Hantouche EG, Azorin M, JP Fraud, Akiskal, HS

This paper presents the preliminary results of a French multi-center study in progress on 100 hospitalized manic (EPIMAN). The aim of EPIMAN is to show the feasibility of validating a new clinical form of mania, such "Dysphoric Mania".

Methodology: It involves 1) training French psychiatrists in 5 sites; 2) construction of a protocol based on criteria of DSM-IV, Akiskal, McElroy et al, Swann et al, as well as instruments like Beigel-Murphy and Ahrean-Carroll (manic scales), modified HAM-D13 / 17 (Depression scale), semi-structrured interview for evaluation of affective temperaments (Akiskal et al), family history and comorbidity (Winokur’s user's friendly criteria); 3) prospective follow-up during a period of 12 months.

Results: Preliminary results are presented on 77 hospitalized manic patients. The rate of "Dysphoric Mania" or MD (defined by the presence of 2 depressive symptoms for "Probable DM" and > 3 for "Definite DM") is 38% of hospitalized manic. DM didn't represent an extreme form of mania (lower score on Beigel-Murphy scale). Significant differences versus "Pure Mania" were obtained on female over-representation (83%); lower frequency of typical manic symptomatology (grandiosity, elation, hyperactivity); longer latency before correct diagnosis; and higher rate of mixed states in the first episodes (25% vs 2%). Finally, higher level of "Irritable Temperament" was observed in the "Probable DM".

Gender differences in bipolar disorder

Authors: Victoria Hendrick, M.D., Lori Altshuler, M.D., Michael Gitlin, M.D.

Psychiatric interviews were obtained on the first 88 consecutive patients presenting for treatment at UCLA's Affective Disorders Clinic. At the time of the interview, clinicians completed database forms that were subsequently used to establish a computer database on the clinic's mood disorder patients. The databases included questions on patients' Axis I and Axis II diagnoses, demographic variables, age of onset of Axis I disorders, number of previous mood episodes and hospitalizations, history of rapid mood cycling, history of substance abuse, medical histories, and family histories of psychiatric illness.

A gender difference that emerged from the database was the greater prevalence of bipolar II disorder in female compared to male patients. While 50% of the 64 bipolar I patients were female, the prevalence rose among the 24 bipolar II patients, of whom 67% were female.

We will also present data on gender differences in the percentage of mood episodes that were depressions vs manias, in the age of onset of bipolar I or bipolar II disorders, in total number of hospitalizations for mood episodes, in family histories of psychiatric illness, and in comorbidity with other Axis I disorders. Gender differences were also identified in patterns and types of medication use.

The Psychosocial Correlates of the Recurrence of Bipolar 1 Disorder from the National Comorbidity Survey

Author: Carolyn A. Holmes, Ph.D., R.N.

Bipolar 1 (BP1) disorder is a recurrent affective psychiatric disorder with a disruptive and debilitating course. Clinical evidence indicates that the frequency of episode recurrence is positively associated with a more severe course and progressive functional deterioration. This study examined the psychosocial risk factors associated with increased recurrence in persons meeting DSM-III-R criteria for a diagnosis of BP1 disorder, using data from the National Comorbidity Survey (NCS) with a representative population sample of noninstitutionalized Americans between the ages of 15 and 54.

A diathesis-stress model was tested to ascertain whether adverse experiences during childhood (e.g., parental psychopathology, relationship difficulties, and violence during childhood) create a vulnerability that predisposes the bipolar respondent to increased risk of recurrence, especially in the presence of certain adult characteristics and circumstances (e.g., comorbidity, traumatic events, chronic stressors, and personality characteristics). The main effects of each childhood and adult predictor and the moderating and mediating effects of adult experiences on childhood adversities to predict recurrence were measured.

Two childhood adversities showed robust direct effects on recurrence, parental psychopathology and childhood abuse. Significant adult risk factors were marital difficulties, interpersonal conflicts, and current traumatic events of an aggressive or financial nature. When all significant childhood and adult predictors were placed in one multivariate model, three factors remained strongly predictive of recurrence. Childhood abuse increased the risk of recurrence over five times, and parental psychopathology and ongoing marital difficulties each doubled the risk. Remarkably, when the effects of multiple risk factors were aggregated, a strong addictive effect was seen. With each additional risk factor the risk of recurrence more than doubled. None of the childhood effects were mediated through adult adversities, but traumatic events reduced the effect size of other adult predictors, suggesting the need to further examine the possibility of a triggering effect for traumatic events.

Clinical Effectiveness of lamoTrigine in Affective Dis0rders

Authors: Scott Hoopes, M.D. Chtd., Mark Snow, Ph.D.

Fourteen males and thirty-three females, 12 to 88 years of age (Bipolar I = 5, Bipolar II = 13, Bipolar N0S = 13, Cyclothymia = 2, Major Depressive Disorders = 10, Mood Disorder = 2, Conduct Disorder = 1) were treated with Lamotrigine. Approximately 83 percent had comorbid diagnoses including substance abuse, anxiety, attention-deficit, eating and cognitive disorders. Seven patients were diagnosed with personality disorders or personality disorder traits.

Lamotrigine was used for patients who could not tolerate other thymoleptics or with disinclination to submit to blood draws, risk of weight gain, or other potentially adverse effects of alternative medications. Twelve patients failed to complete an adequate therapeutic trial because of noncompliance, failure to follow-up, or a move from the area . Follow-up assessments were available for twenty-eight patients and pending for two others. Doses from 25 to 200 mg per day taken once-at-night or twice-a-day were used. Fifteen of twenty-eight were treated with less than 100 mg per day and three with 200 mg per day. Nine patients took lamotrigine only. Combinations of lamotrigine with other medications were generally well-tolerated. Two patients discontinued because of rashes, one because of headaches, and two because of agitation. Twenty patients showed significant improvement and eight did not. Five of the nonresponders had Major Depression with or without a psychosis. Five of eight patients with no comorbid diagnases improved. Patients often reported improvement as early as the first week with doses from 25 to 100 mg per day. Patients with Bipolar I responded as well as Bipolar II patients (four of four and six of eight respectively).

Lamotrigine used for bipolar disorders often produced antidepressant effects, showed rapid response at low doses, was well-tolerated, and generally combined well with other psychotropics. Starting at 25 mg and advancing slowly minimized side effects. Many responders were younger women with rapid cycling Bipolar II who improved within the first two weeks of treatment at doses from 25 to 50 mg per day.

Guanfacine and Juvenile Bipolar IllnesS

Authors: J.P. Horrigan, M.D. and L.J. Barnhill, M.D.

Guanfacine hydrochloride (Tenex) is an alpha-2 adrenergic agonist which has received recent attention in the field of child and adolescent psychiatry due to its apparent benefits in managing attention-deficit/ hyperactivity disorder (ADHD), tic disorders, and posttraumatic stress disorder. The initial reports noted minimal side effects. This poster details six cases of adverse responses to guanfacine, drawn from an initial clinic sample of 95 outpatient boys and girls aged 8 to 15 years who were seen in a university-based developmental neuropsychiatric clinic. In each case, the patient met formal DSM-IV criteria for ADHD while four out of six also met criteria for Tourette's Disorder. Within 72 hours of initiation of guanfacine therapy, drastic changes in mood and behavior occurred in each of these individuals, culminating in states that resembled hypomania and mania, including elevated mood, poor sleep hygiene, and hypersexuality. The dose of guanfacine ranged from l to 2 mg/day. Later investigation revealed that all of the youngsters had clinical and/or familial risk factors for bipolar disorder. The authors speculate about the possible mechanisms behind these side effects, and suggest that bipolar disorder may be a relative contraindication to guanfacine therapy.

Suicide and Other Causes of Death in Patients with Bipolar and Unipolar Illness

Author: Eyd Hansen Hr yer

Several studies have found an increase in mortality in patients with bipolar and unipolar illness, compared with the general population. The single most important cause of this is suicide. Furthermore, the studies have revealed an increase in mortality from "natural" causes, especially due to cardiovascular diseases. In studies comparing the mortality of unipolar and bipolar patients, a tendency towards an increase in mortality due to "natural" causes, has been found in patients with bipolar illness. When suicide rates in bipolar and unipolar illness have been compared, the results have been contradictory. Generally, these studies have limited statistical power, especially when dividing groups according to age, gender, duration of illness, and bipolar/unipolar illness. In this project we study the mortality in patients with bipolar/unipolar illness in a large population-based sample of first-admitted patients compared with the general population in relation to age, gender, duration of illness, cause of death, and the time elapsed between discharge from a psychiatric hospital and time of death.

Methods: This project includes a total nationwide sample of approximately 20,000 patients with bipolar and unipolar manic-depressive illness, followed up to 25 years. Mortality is compared with the general population using the person-years method, calculating the SMR. Bipolar and unipolar patients are compared using survival analysis. The project is based on data from a record linkage between two nationwide Danish registers, available in the Danish Database for Psychiatric Epidemiological Research.

Results: Are not yet available. Data is currently being analyzed.

A Standard Education Programme for Patients at Lithium Maintenance Treatment*

Authors: E.A.M. Knoppert-van der Klein, C.A.L. Hoogduin, A.S. van Peski-Oosterbaan, P. K` lling, and J.R. Beck-Lie A Fat.

Research Questions: Do knowledge and attitudes about lithium treatment improve by an education programme (a videotape and a written hand-out) and does compliance improve?

Patients and Methods: Forty-six patients on lithium in remission were at random divided into two groups; five times (every six weeks) the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnarie (LAQ) (both translated in Dutch), a list of side-effects and lithium levels were assessed: Group 1 received the programme at second visit, group 2, six weeks later.

Results and Conclusions: The educational programme showed a positive effect on patient knowledge and attitudes about the lithium treatment. Both effects decline slowly in time. No increase in reported side-effect was found.

*This study is a replication with permission of the study of Peet & Harvey, British Journal of Psychiatry 1991, 158, 197-204

A Case of Ultra-rapid Cycling Bipolar Disorder With Frontal Epilepsy in a 13 Year Old Boy

Authors: Kochman, F, Ducrocq, F, Parquet, PJ

We report the case of a 13 year old adolescent, hospitalized in our department (Child and Adolescent Psychiatry - Professor PARQUET) because of a major depressive disorder with suicidal ideas. After three days, his behaviour changed, with disappearance of depressive mood and appearance of pleasurable activities with a high potential for painful consequences (combined with irritability and aggressiveness), sexual indiscretions, grandiosity, decreased need for sleep, flight of ideas, marked impairment in social functioning. Using Kiddie-SADS-R (according to DSM-IV classification), the young patient fulfilled either criteria for Major Depressive Disorder or for Hypomanic Episodes (twice for Manic Episode), with a period of approximately one week for each episode. Plus, the adolescent had brief and sudden crisis characterized by aggressiveness, sexual concerns and sexual acts mimics, atypical upper limbs movements, and postcritical confusion.

Electroencephalography revealed frontal seizures. This patient has been dramatically improved after a Valproate treatment.

We hypothesize that bipolar disorder in children and adolescents is not a rare disease but is just massively underdiagnosed. Besides, this disease should often occur at this age by ultra-rapid cycling. This fact could also explain its misdiagnosis.

Anyway, what is the relation between this bipolar disorder and frontal seizures ?

We propose different hypotheses according to the literature.

Efficacy of Valproate/Valpromide in Ultra-rapid Cycling Bipolar Disorders n Children and Adolescents

Authors: Kochman, F, Ducrocq, F, Parquet, PJ

Bipolar disorder is a diagnosis rarely given in childhood and adolescence. A regularly biphasic disorder is described in 4 children and adolescents (9, 11, 12 and 13 years old). It was characterized by several hours to several days (period ranging from 4 hours to 10 days) of manic, hypomanic episodes, or major depressive disorders. According to Kiddie-SADS-R semi-structured interview (DSM-IV), these young patients presented mixed episodes included in a bipolar disorder.

Anyway, we think that these young patients present either (hypo)manic episodes or major depressive disorders during a very short period of time (sometimes lasting a few hours only).

Nevertheless, should we consider these children and adolescents as patients suffering from ultra-rapid cycling bipolar disorders, which could be considered as a new entity, or a form of early-onset bipolar disorder ?

We have been prescribing Valpromide for 3 patients, Valproate for one. We observed a dramatic improvement within 2 weeks (CGI score at 5.75 before, and at 1.25 after treatment). According to a second Kiddie-SADS-R assessment, none of them still met criteria for a Mood Disorder after treatment. They are still asymptomatic after at least 4 months of treatment.

This case report should be followed by further studies to validate this new clinical entity, and by a double-blind placebo-controlled trial.

Total Sleep Deprivation and Consecutive Sleep-phase-advance in bipolar Versus Unipolar Depression: Effects on Psychopathology

Authors: K` nig, A. Riemann D., Hohagen F., Kiemen A., Hornyak M.,
Steffes P., Voderholzer U., Berger, M.

Total sleep deprivation (TSD) has an immediate antidepressive effect in 60 % of depressed patients. In a pilot study we were able to show that the usual relapse into depression after successful TSD could be prevented in approximately 60 % of depressed patients by a succeeding sleep phase advance therapy (SPA). This strategy was based on studies which showed that a phase advance of the sleep period alone acts antidepressive, that naps in the morning after successful TSD have stronger depressiogenic effect than in the afternoon and that sleep deprivation in the second half of the night improves mood, but not sleep deprivation in the first half of the night. Additionally, we tested the effect of phase advance in bipolar depressed patients.

Methods: 33 inpatients (45,2? 13,4 yrs) with MDD (subtype melancholia; DSM-III-R), all responders to TSD, have participated in the study. 22 of the patients suffered from uni-, 11 from bipolar MDD. Both groups did not differ concerning age, severity of depression, number of episodes and duration of current episode. Depressed mood was measured by the 21- and 6-HAMD. Patients were considered as responders to TSD, SPA or SPD, if their 6-HAMD showed an at least 30 % reduction compared to the baseline value. Phase advance: bedtime after TSD from 5.00 p.m. until midnight and then a daily one hour delay of the sleep phase finished with the conventional bedtime from 11.00 p.m. till 6.00 a.m.

Results: 18 out of 22 patients with unipolar depression and 8 out of 11 patients with bipolar depression finished the SPA. The 6-HAMD of the unipolar MDD group improved by 53,1 ? 39,1 %, the improvement in the bipolar MDD group was 62,7 ? 34,5 %. Both groups did not show any significant difference by t-test in the response to neither TSD (p = 0,909) nor to SPA (t-test: p = 0,422).

Conclusion: TSD followed by SPA seems to present an effective method for mood stabilization. Results show similar improvement of unipolar versus bipolar MDD. This useful strategy for the treatment of depression should be used as often in bipolar as in unipolar depressed patients.

Prodromes, coping strategies, insight and social functioning in bipolar affective disorders

Author: Dominic Lam, Ph.D.

Forty patients suffering from bipolar affective disorder were interviewed for their prodromes of depression and mania, their coping strategies for these prodromes, their levels of insight and their levels of social functioning. A quarter of subjects reported that they could not detect any early warnings of depression compared with only 7.5% of subjects who reported that they could not detect prodromes of mania. There were significantly more high functioning subjects in the good coping group for prodromes of mania. More high functioning subjects were also present in the good coping group for prodromes of depression but the difference just failed to reach statistical significance. More subjects in the good coping group for prodromes of mania reported the spontaneous use of behavioural techniques, for example restraining themselves from excessive behaviour, engaging in calming activities and taking extra time to rest or sleep when they detected prodromes of mania. Similarly, subjects in the good coping group for prodromes of depression used behavioural techniques such as keeping busy. However some subjects also reported cognitive techniques of distraction from negative thoughts and recognising unrealistic thoughts and evaluating if these thoughts were worth worrying about. Subjects' current levels of depression, coping with prodromes of mania, insight and ability to recognise early warnings for depression contributed significantly to their levels of social functioning.

Cognitive Therapy for Manic Depression: a pilot study - end of therapy outcome

Author: Dominic Lam, Ph.D.

Aim of the Project: The pilot study aims at using cognitive behavioural strategies for the treatment of manic depressive illness in conjunction with pharmacological approach. We have recruited bipolar patients who are on prophylactic medication and yet are still at risk of relapsing.

Design: The pilot study is a randomised controlled design. Twenty four subjects suffering from manic depression were randomly allocated to an experimental and a control group. Subjects in the control group have usual outpatient treatment. Twelve to twenty sessions of cognitive therapy with be given to subjects in the experimental group. Therapy is based on Beck et al.'s (1979) cognitive model for affective disorder as well as specific techniques developed for bipolar patients. Specifically subjects are taught cognitive behavioural skills to: 1. deal with mood swings, 2. monitor early warning signs and manage them,

3. promote insight and compliance of medication, 4. promote a routine and good self management: 5. promote social functioning, 6. increase sense of control, 7. tackle any sense of stigma.

Inclusion criteria: 1. DSM-IV Bipolar I or Bipolar II Disorder, 2. at least two episodes of mania/hypomania in the last two years or three or more past episodes, 3. no history of non-affective non-organic psychosis or schizo-affective disorder, 4. no periods of alcoholism or drug abuse in the past year, 5. on regular medication, 6.age 18 to 65,

7. currently not in a manic episode or deeply depressed (BDI<29; MAS <9),

8. currently not in any psychological therapy, 9. no previous CBT experience.

Methods: Instruments: 1. S.A.D.S. covering the period of interest, BDI, MAS, Internal State Scale; 2. MRC Social Performance Schedule for interviewer rating (Harry et al. 1983); 3. Social adjustment scale (Cooper et al. 1982); 4. Insight interview adapted from David et al. (1992); 5. Views of Manic Depression (Hayward et al. unpublished); 6. Self-control behavior schedule (Rosenbaum, 1980); 7. Early warning and coping interview (Lam and Wong, unpublished); 8. Coping questionnaire (Wong and Lam, unpublished); Self-concept questionnaire (Robson et al., 1989); 10. Significant Others Scale (Power et al. 1988); 11. Mill Hill Verbal Scale (only on recruitment). Subjects were assessed at recruitment, and at six and twelve months. The above measures at recruitment are repeated with the S.A.D.S. covering the relevant period.

Outcome: Monthly mood rating as well as numbers of bipolar episodes during the first six months produced promising results.

Factors Associated with Poor Psychosocial Functioning among Children of Parents with Bipolar Disorder

Authors: Lapalme, M. and Hodgins, S.

The present study was designed to evaluate the psychosocial functioning of children of parents with bipolar disorder as compared to that of children of parents with no mental disorders and to identify associated factors. Forty-nine parents with a confirmed diagnosis of bipolar disorder, their spouses (biological co-parents of the child), and their 67 children were compared to 40 couples with no mental disorders and their 57 children. The children, aged five to twelve years old, were rated independently by both parents on the Child Behavior Checklist. Comorbid disorders in the bipolar parent (SCID I and II), mental disorders in the other biological parents (SCID I and II), marital adjustment (Dyadic Adjustment Scale), and parenting practices (Parenting Dimensions Inventory) were assessed. Proportionately, more of the children of parents with bipolar disorder than the children of parents with no mental disorders were rated as having psychosocial problems within the clinical range. Among both groups of families, parenting practices, but not marital adjustment, were found to be related to the presence of difficulties among the children. Within bipolar families, the presence of a personality disorder in the bipolar parents was associated with impaired psychosocial functioning in the children, particularly when the bipolar parent is the mother. Neither the presence of a comorbid axis I disorder in the bipolar parent, nor the presence of a disorder (Axis I or II) in the co-parent were found to be related to problems among the children. Results suggest that in childhood, impaired psychosocial functioning among children of parents with bipolar disorder is more strongly related to comorbid personality disorder and to poor parenting practices than to parental bipolar disorder per se.

Comparison of Functioning in Children of Parents with Bipolar Disorder (BPD) and Parents with no Serious Mental Disorder (NMD)

Authors: LaRoche, Catherine; Hodgins, Sheilagh; Marrache, Myriam
and Lapalme, Micheline

In addition to recent advances in the etiology and treatment of adult BPD, there remains a need to increase understanding and develop preventive interventions for the children of these adults. Many of these children develop different forms of psychopathology at younger and younger ages. These childhood disorders may represent antecedents of adulthood disorders and/or reactions to living with a mentally disordered parent.

This poster presents initial findings from a prospective longitudinal study comparing the development of children of parents with BPD and children of parents with no mental disorder (NMD). The experimental group includes 57 adults with a confirmed diagnosis of BPD, their spouses and 79 children. The comparison group includes 51 couples with NMD and their 77 children.

Measures for parents include a Diagnostic Interview (SCID), a Parental History of Mental Disorder, and measures of parental personality traits, parenting, social support, coping skills and a measure for family violence (CTS). Childrens' Diagnostic and Functional Measures include the Dominic (Valla et al.), Child and Parent versions of the Child Assessment Scale (CAS) (Hodges) and the Child and Adolescent Functional Assessment Scale (CAFAS) (Hodges). These interview protocols were chosen because of their appropriate fit with the developmental limitations of young children (ages 5 to 12) and for their good psychometric properties.

Initial findings show a consistent pattern of parental impairment rates ranging from the highest rate among parents with BPD, medium rates in their spouses, and the lowest rates among parents with NMD. Few diagnoses were assigned to the total child sample. However, children of BPD parents showed more impairment in both symptomatic and functional areas than children with NMD. Considerable disagreement existed between informants regarding childrens' functioning.

Genetic evidence for a bipolar disorder subtype

Authors: MacKinnon DF, Xu J, McMahon FJ, Simpson SG, Stine OC,
McInnis MG, DePaulo JR

Panic disorder frequently cosegregates with bipolar disorder in some families. In these families, we have proposed that a high risk for panic disorder may be a marker for a genetically distinct subtype of bipolar disorder. We now test this hypothesis on a sample of 28 families ascertained, psychiatrically interviewed, genetically analyzed, and reported on elsewhere as part of a genome-wide screen for loci linked with bipolar disorder. In our initial study, we found evidence of linkage using 31 markers along chromosome 18. Here, we have reevaluated these linkage results using multipoint lod score and nonparametric linkage (NPL) analyses, stratifying the sample into three groups: 1) five families in which the bipolar proband ofthe family was diagnosed as having panic disorder (RDC inclusion criteria); 2) six families in which the proband had panic attacks, but did not meet criteria for panic disorder; 3) families in which probands did not have panic disorder or any history of panic attacks. Only family members with BPI or BPII were considered affected, and included in the analysis. Multipoint NPL Z-scores were in the range of 4.0-4.8 (p=0.003-0.001) for region from D18S42 to D18S61 on 18q, only for the group of families in which the proband had panic disorder. Scores for the second group were intermediate, ranging from 1.5-2.0 (p=0.3-0.04) in the same region, while scores for the third group in this region were all negative (-0.5 to -2.0). The maximum multipoint lod score for group 1 was 2.93, at Dl8S61. This study provides evidence for genetically distinct subtypes of bipolar disorder, distinguished clinically by a difference in the risk of comorbid panic disorder in probands and affected family members. Under-standing this finding in light of other phenotypic divisions (e.g., paternal/maternal pedigrees) requires further study.

Initial Definitive Treatment of Mania in a Psychiatric Emergency Service

Authors: Lucian Manu, M. D. and Michael H. Allen, M. D.

The previously available antimanic agents, lithium and the neuroleptics, have significant limitations in the Psychiatric Emergency Service. More recently, divalproex sodium (DVX) has been shown to be superior to placebo and comparable to lithium. DVX is better tolerated and appears to have a rapid onset after achieving therapeutic blood levels. A loading strategy has been developed, which seeks to take advantage of the favorable side effect profile and rapid onset. Three published reports suggest the effectiveness of this approach.

The Bellevue Comprehensive Psychiatric Emergency Program (CPEP) treats patients intensively for up to three days in an Extended Observation Unit (EOU). Patients are evaluated psychiatrically and medically on EOU Day 1. If no contraindications emerge, consenting patients receive DVX 20 mg/kg in divided doses by the end of Day 1. Patients are under close medical and nursing supervision at all times. Patients are reevaluated on Day 2, a 12 hour VPA trough level is obtained, and the dosage sometimes adjusted for Days 2 and following. Lorazopam 2 mg is available on an as needed basis. Patients are again evaluated on Day 3 for final disposition. If sufficiently improved, patients are discharged to the community with aftercare, provided by CPEP, if necessary. If insufficiently improved, patients are admitted to a Bellevue inpatient unit.

Using routine hospital data sources, all patients who received DVX in the EOU from September 1995 to July 1996 were identified. In order to measure response to this strategy, changes in mental status, day, time, dosage, and route of adjunctive medications and inpatient admission rate were assessed. For patients discharged from CPEP to the community, recidivism at 30 days and community survival analysis are also reported. Urine toxicology, other significant laboratory results, and side effects are described.

Bipolar Disorder in the Latter Half of Life: Symptom Presentation, Global functioning, stability, and age of Onset in a Community Sample

Author: Suzanne Meeks, Ph.D.

Relatively little is known about the manifestations of bipolar disorder in late life. Many of the reports on late-life bipolar disorder are clinical case reports, usually drawn from inpatient expenences. The majority of empirical studies also have focused on a hospital-based population, and many have focused on late-onset mania or bipolar disorder. By contrast, the present paper focuses on a community-based sample of middle-aged and older adults diagnosed with bipolar disorder according to Research Diagnostic Criteria (RDC). Participants were 87 individuals who took part in a larger eight-month prospective study of severe mental illness in later life. All participants had received services in the five previous years from one of two community mental health centers in a 12 county region surrounding the Louisville, KY metropolitan area: they were selected randomly from current and former client lists of the centers. All were over the age of 40, were designated as having a severe mental illness by state criteria, and did not have primary diagnoses of substance abuse disorders. Psychiatric history and current functioning were assessed using the SADS lifetime version.

The average age of the sample was 53.60 (SD=9.78), with a range from 40 to 78. They were 73.6% women and 26.4% men, had a mean education of 12.41 years (SD=3.56) and median income under $10,000 per year. Participants were interviewed three times at four-month intervals. At the time of the first interview, 1/4 were not in an episode of illness; 1/4 were in a new episode of illness of less than five years duration, and the remainder were divided among more chronic or cycling conditions. Approximately one-third remained stable across study intervals in either an illness-free state or in a residual state with minimal symptoms; 35% were stably ill, and about a third were unstable across the eight months of the study. In spite of the fact that the majority were in acute or chronic episodes, only 34.5% were receiving lithium and 37.9% were receiving antidepressants. A similar number (36.8%) were receiving neuroleptic medications. One-third were receiving some form of psychotherapy. Normative presentation was more depressive than manic symptoms, with few psychotic symptoms. Age was unrelated to symptom presentation. Treatments received were unrelated to short-term stability.

Participants had experienced on average 14.49 prior manic episodes, and 17.77 depressive episodes. The mean duration of their longest manic episode was 120 weeks and for depressive episodes 141 weeks, although there was tremendous variation and the modal episode length was much shorter. The average age of onset of any symptoms was 24.84; the mean age at the first identifiable manic episode was 34.95, with the first depressive episode occurring approximately 5 years earlier. Age of onset was unrelated to short-term stability, which was related only to the prior number of depressive episodes experienced. However, age of onset was strongly related to global functioning, accounting for 13% of the variance in GAS scores with age controlled. No other aspects chronicity of illness were related to GAS once age of onset was entered.

This study of community-dwelling middle-aged and older adults with bipolar disorder is unique in its focus on community-dwelling individuals with early-onset bipolar disorder and long-term episodic or chronic illness. In this group of individuals, there is great variability in functioning and symptom presentation, although the norm is significant impairment and limited socioeconomic resources. Consistent with previous literature, age of onset appears to be an important predictor of global functioning. Despite the fact that the sample was identified through mental health agencies, up to two-thirds may not have been benefitting from appropriate pharmacological or psychosocial treatments.

*This study was supported by grant #R29 MH44787 from the National Inst. of Mental Health

The psychoeducational approach on the treatment of bipolar patients

Authors: Ricardo Alberto Moreno & Ana Claudia Fontes de Andrade

One of the main difficulties faced on the clinical practice with bipolar patients is the high rate of noncompliance. Recent studies have shown the efficacy of the psychoeducational approach, in addition to other treatment modalities on the improvement of compliance levels and quality of life of these patients and their families. This research aims to study the effect of this approach combined with lithium therapy in a 10 weekly session group of outpatient clients in a university hospital in Brasil. There is a control group, assisted individually in medical appointments for outcome comparison purposes. Outcome will be presented through the assessment of symptomatology, social adjustment, compliance and level of information. The assessment is being done eight weeks prior to the group sessions, at the end of the intervention and at the third, sixth and twelfth month after the end of the program for maintenance checking purposes.

Gender Differences Among Late-Onset vs. Early-Onset Bipolars

Authors: Myers, Diane S., Stabb, Sally D., & Rubin, Linda

The present study was undertaken to evaluate gender differences in symptom presentation, family history, and role of stressful life events in late-onset vs. early-onset bipolar disorder. Post (1992) has identified 10 characteristics of affective illness that may parallel the longitudinal course of bipolar disorder. Using a qualitative patternmatching design, medical records of late-onset bipolar patients were compared to early-onset bipolars using Post's 10 characteristics. Archival medical records were evaluated on 156 bipolar I patients at a large northeastern psychiatric hospital. Retrospective review of medical records on a subgroup of 35 late-onset bipolar I patients, including 15 late-onset females and 20 late-onset males, were compared with records of 121 earlyonset bipolar I patients, including 84 early-onset females and 37 early-onset males. Results partially supported the theoretical hypotheses of the study. Late-onset bipolar patients were found to have a less frequent family history of affective illness, and male late-onset bipolar patients had a more frequent association of stressful life events with all bipolar episodes than early-onset or female late-onset bipolars. In addition, late-onset bipolar patients reported a higher percentage of paranoid delusions, irritability/anger, and mixed mania symptoms as part of the symptom picture than early-onset bipolars. Using Post's 10 characteristics, results revealed that females more frequently had early experiences that may have predisposed them to later bipolar episodes than males. Late-onset females demonstrated other differences in bipolar history, including heightened vulnerability to recurrent episodes, more conditioned compensatory reactions, and more positive response to carbamazepine administration than late-onset males or early-onset bipolars. Thus, findings suggest that there are gender differences among late-onset vs. early-onset bipolar patients. More complete findings of the study and implications for further research will be presented.

Coping Resources and Life Functioning of Hospitalized People with Bipolar Disorder

Authors: L.E. Pollack, PhD, K. Kouzekanani, PhD, S. Harvin, MSN,
and R. V. Varner,MD

Purpose: The coping resources and life functioning of hospitalized people with bipolar disorder were studied with respect to race, chronicity, and gender.

Methods: Seventy-one subjects (65% female, 35% male; 63% Euro-American, 37% African-American; average age 35.6 years), diagnosed using DSM-IV criteria, were recruited from a state- and county-funded acute psychiatric hospital. The Coping Resources Inventory (CRI) was used to measure subjects' self-reported coping resources in five domains (cognitive, social, emotional, spiritual/philosophical, physical), and a total score. The Behavior and Symptom Identification Scale (BASIS-32) was used to measure subjects' self-reported difficulty in symptoms (depression/anxiety, impulsive/addictive behavior, psychosis) and functioning (relation to self/others, daily living/role functioning), and a grand mean score. Data were collected during the most recent episode, and prior to beginning an inpatient bipolar group therapy program.

Results and Conclusions: The Euro-American group reported significantly higher degrees of difficulty in the major areas of relation to self/others, depression/anxiety, daily living/role functioning, impulsive behavior, and on the BASIS-32 grand mean score, than did the AfricanAmerican group. Euro-Americans also reported significantly lower levels of coping resources in the cognitive and emotional domains, and on the CRI total score, when compared to the African-American group. These findings indicate that the Euro-American group perceived greater impairment and fewer coping resources than the African-American group. Subjects who had three or fewer hospitalizations (acute group) had significantly: (a) higher scores on their perceived degree of difficulty in relation to self/others, daily living, and on the grand mean BASIS-32 score; and (b) lower scores on the cognitive and emotional coping resource dimensions, and on the total CRI score, than did those subjects who had more than three hospitalizations (chronic group). In comparison with the chronic group, the acute group may have been more aware of, or affected by, their deterioration in life functioning, and/or were not hospitalized until deterioration was more pronounced. Significant gender differences on coping resources, as well as behavior and symptom identification, were not evident, indicating one area of homogeneity in this sample.

Neuropsychological Profiles in Bipolar Affective Disorder

Authors: Kristin B. Powell, David J. Miklowitz, & Jeffrey A. Richards

Brain dysfunction and cognitive deficits have long been correlated with clinical outcome and course of illness in schizophrenia. However, research in the neuropsychology of bipolar disorder has been limited. The present study will present neuropsychological data on a group of bipolar patients varying in severity of illness and subtype. Based upon a previous review of the literature (Powell & Miklowitz, 1994), these assessments focus on tasks related to frontal lobe functioning, and take place during periods of relative symptom remission, so as to minimize purely state-related cognitive deficits.

Subjects received an assessment battery consisting of the following measures: the Wisconsin Card Sorting Test; the California Verbal Learning Test; the Behavioral Dyscontrol Scale; Halstead-Reitan Finger Tapping; Digit Span, Vocabulary and Block Design (WAIS-R). Subjects have also been administered two experimental measures proposed to tap into more subtle aspects of prefrontal functioning: the Delayed Alternation Response Task, a measure of spatial working memory (Gold, Berman, Randolph, Goldberg, & Weinberger, 1996), and the "gambling task" developed by Antonio Damasio's research team (Bechara, Damasio, Damasio, & Anderson, 1996) as a potential indicator of orbitofrontal functioning.

Within-group analyses (N = 20) will examine the relationships between subjects' performance on neuropsychological measures and patient characteristics including diagnostic subtype (Bipolar I versus II), presence or absence of psychotic states during episodes, medication regimen (treated versus not treated with anticonvulsants) and neuropsychological risk factors (severe substance abuse, head injury, and other neurological insults). Results will be discussed in terms of their implications for diagnostic subtyping, prognosis and treatment of the "cognitive" correlates of bipolar disorder.

Cognitive Diathesis-Stress Interactions as Predictors of Bipolar and Unipolar Symptomatology

Authors: Noreen A. Reilly-Harrington, Lauren B. Alloy, and David M. Fresco

While extensive research has investigated the role of cognitive processes and life events in unipolar depression, comparatively little is known about the role of such psychosocial factors in the course of bipolar mood disorders. However, the logic of cognitive diathesis-stress models and previous preliminary research suggest that cognitive vulnerability factors may predispose individuals with bipolar mood disorders to manic/hypomanic and depressive episodes when confronted with life events. The current study examined the interaction of cognitive style and life events in predicting the depressive and manic/hypomanic mood swings of undergraduates meeting RDC lifetime diagnoses (based on a modified-SADS-Lifetime interview) for Bipolar I (n=18), Bipolar II or Cyclothymia (n=43), Unipolar Depression (n=102), or no lifetime diagnosis (n=43). At two time points (averaging 1 month apart), subjects completed measures of depressive and manic symptoms (Beck Depression Inventory, MMPI Mania Scale), cognitive styles (Attributional Style Questionnaire, Dysfunctional Attitudes Scale), and major and minor, positive and negative life events (Life Experiences Survey, Hassles and Uplifts Scale). Hierarchical regression analyses indicated that subjects' attributional styles (as assessed at Time 1) interacted significantly with life events occurring between Times 1 and 2 to predict depressive symptoms at Time 2. Furthermore, support was found for the specific vulnerability hypotheses of Beck's Theory and Hopelessness Theory in which individuals are thought to be most susceptible to depression when experiencing events to which they attach strong personal meaning or significance. Hierarchical regression analyses indicated a significant interaction between autonomous cognitive style (as assessed at Time 1) and the occurrence of achievement-related stressors between Times 1 and 2 in predicting depressive symptoms at Time 2. While the interaction between cognitive style and life events in predicting manic/hypomanic symptomatology was nonsignificant in the current study, a significant main effect was found for cognitive style.

Comparisons of Cognitive Styles Across the Bipolar and Unipolar Spectrums

Authors: Noreen A. Reilly-Harrington, La