Abnormal left superior temporal gyrus volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study

Abnormalities in left superior temporal gyrus (STG) have been reported in adult bipolar patients. However, it is not known whether such abnormalities are already present early in the course of this illness. Magnetic resonance imaging (MRI) morphometric analysis of STG was performed in 16 DSM-IV children and adolescents with bipolar disorder (mean age+/-SD 15.5+/-3.4 years) and 21 healthy controls (mean age+/-SD 16.9+/-3.8 years). Subjects underwent a 3D spoiled gradient recalled acquisition MRI examination. Using analysis of covariance with age, gender and intra-cranial brain volume as covariates, we found significantly smaller left total STG volumes in bipolar patients (12.5+/-1.5 cm(3)) compared with healthy controls (13.6+/-2.5 cm(3)) (F=4.45, d.f.=1, 32, P=0.04). This difference was accounted for by significantly smaller left and right STG white matter volumes in bipolar patients. Decreased white matter connections may be the core of abnormalities in STG, which is an important region for speech, language and communication, and could possibly underlie neurocognitive deficits present in bipolar patients.     

Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder

Imaging studies indicate smaller orbitofrontal cortex (OFC) volume in mood disorder patients compared with healthy subjects. We sought to determine whether child and adolescent patients with bipolar disorder have smaller OFC volumes than healthy controls. Fourteen children and adolescents meeting DSM-IV criteria for bipolar disorder (six males and eight females with a mean age+/-S.D.=15.5+/-3.2 years) and 20 healthy controls (11 males and nine females with mean age+/-S.D.=16.9+/-3.8 years) were studied. Orbitofrontal cortex volume was measured using magnetic resonance imaging. Male bipolar patients had smaller gray matter volumes in medial (p=0.044), right medial (0.037) and right (p=0.032) lateral OFC subdivisions compared to male controls. In contrast, female patients had larger gray matter volumes in left (p=0.03), lateral (p=0.012), left lateral (p=0.007), and trends for larger volumes in right lateral and left medial OFC subdivisions compared with female controls. Male patients exhibit smaller gray matter volumes, while female patients exhibit larger volumes in some OFC sub-regions. Gender differences in OFC abnormalities may be involved in illness pathophysiology among young bipolar patients.     

Event related oscillations in euthymic patients with bipolar disorder

Bipolar disorder involves dysfunction in gamma amino butyric acid (GABA)/glutamatergic systems and neural circuits that regulate cognitive processing. Valproate, a mood stabilizing anticonvulsant, modulates GABA/glutamate and shows neuroprotective effect. Electroencephalographic oscillatory activity assessment is an alternative brain imaging technique with high time resolution. It presents integrative brain functioning. We aimed to assess the oscillatory responses of patients with bipolar disorder in euthymic state of bipolar disorder and the changes after treatment with valproate. Event related potentials to visual odd-ball paradigm in 10 euthymic medication free, bipolar patients were measured before and after 6 weeks of valproate monotherapy and compared with sex- and age-matched healthy controls. Delta frequency bands, as representative of signal detection and decision-making, were obtained by digital filtering. At baseline, patients showed higher delta responses to target stimuli in all but significantly left frontal channels in comparison to controls. After 6 weeks of treatment, delta responses decreased significantly in central frontal (Fz) (p: 0.028), left frontal (F3) (p: 0.028), left (T3) (p: 0.015), right anterior (T4) (p: 0.011), and left posterior temporal (T5) (p: 0.011) channels compared to baseline and became no different to the controls, which did not differ between two assessments. The findings point to a diffuse increase in low frequency electrical activity which was prominent in the left frontal location in euthymic patients with bipolar disorder. Reduction of the electrical activity of the left frontal and bilateral anterior temporal areas with treatment may be through modulation of glutamatergic and GABAergic mechanisms and indicative of valproate's neuroprotective effect.     

Quantitative proton magnetic resonance spectroscopy of the bilateral frontal lobes in patients with bipolar disorder.

BACKGROUND: Using 31P and 1H magnetic resonance spectroscopy (MRS) we previously reported that phosphocreatine was decreased in the left frontal lobe and choline-containing compounds were increased in the basal ganglia in the depressive state in patients with bipolar disorder. We applied quantitative 1H-MRS for further characterization of biochemical alteration in the frontal lobes of bipolar patients. METHODS: Twenty-three bipolar patients and 20 normal controls were examined by 1H-MRS with a 1.5T MR system. All patients were examined in the euthymic state, and eight patients were also examined in the depressive state. Volumes of interest of 2.5 x 2.5 x 2.5 cm were selected in the left and right frontal lobes. Absolute concentrations of N-acetyl-1-aspartate, creatine plus phosphocreatine, and choline-containing compounds were calculated from each metabolite peak. RESULTS: Creatine concentration in the left frontal lobe in bipolar patients in the depressive state was significantly lower than that in the euthymic state. Creatine concentration in the right frontal lobe in the male patients was significantly higher than that in the female patients and a similar trend was also found in the control subjects. CONCLUSIONS: We found a state-dependent change of creatine metabolism in the left frontal lobe of bipolar patients. The present results are compatible with our previous report of decreased phosphocreatine measured by 31P-MRS in the left frontal lobe in bipolar disorder. We also found an effect of gender on the creatine concentration. There may be a gender difference in creatine transport function into the brain.     

Influence of citalopram and environmental temperature on exercise-induced changes in BDNF

Differences and similarities in microstructural white matter alterations between bipolar I and bipolar II disorder were investigated. Twelve patients with bipolar I disorder, 12 patients with bipolar II disorder and 22 healthy controls underwent diffusion tensor imaging. Fractional anisotropy (FA) and mean apparent diffusion coefficient (ADC) maps were compared between groups using voxel-based whole brain analyses. Both bipolar I and II groups had a FA decrease in the corpus callosum, cingulate and right prefrontal regions, and a ADC increase in the medial frontal, anterior cingulate, insular and temporal regions, compared to controls. The bipolar I group had a FA decrease in the right temporal white matter and a ADC increase in the frontal, temporal, parietal and thalamic regions, compared to the bipolar II group. The results suggest disrupted integrity of commissural fibers and white matter in the anterior paralimbic structures in bipolar disorder. Relative sparing of the dorsal system and long association fibers may differentiate bipolar II from I disorder.     

Abnormal corpus callosum myelination in pediatric bipolar patients

BACKGROUND: Decreased signal intensity in the corpus callosum, reported in adult bipolar disorder patients, has been regarded as an indicator of abnormalities in myelination. Here we compared the callosal signal intensity of children and adolescents with bipolar disorder to that of matched healthy subjects, to investigate the hypothesis that callosal myelination is abnormal in pediatric bipolar patients. METHODS: Children and adolescents with DSM-IV bipolar disorder (n=16, mean age+/-S.D.=15.5+/-3.4 y) and matched healthy comparison subjects (n=21, mean age+/-S.D.=16.9+/-3.8 y) underwent a 1.5 T MRI brain scan. Corpus callosum signal intensity was measured using an Apple Power Mac G4 running NIH Image1.62 software. RESULTS: Bipolar children and adolescents had significantly lower corpus callosum signal intensity for all callosal sub-regions (genu, anterior body, posterior body, isthmus and splenium) compared to healthy subjects (ANCOVA, all p<0.05, age and gender as covariates). LIMITATIONS: Relatively small sample size. CONCLUSIONS: Abnormalities in corpus callosum, probably due to altered myelination during neurodevelopment, may play a role in the pathophysiology of bipolar disorder among children and adolescents.     

Decreased activation of the anterior cingulate in bipolar patients: an fMRI study

BACKGROUND: Previous neuroimaging investigations of patients with bipolar disorder have reported abnormalities of the frontal subcortical network. The role of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) in bipolar disorder are not clear, although both regions have been shown to be components of a neural network which plays a critical role in the completion of tasks requiring self-monitoring and inhibition, functions often noted to be altered in bipolar patients. fMRI studies have helped clarify the role of specific subdivisions of the ACC and the DLPFC during the performance of cognitive challenges, including the Stroop color word test. To date, studies that have examined ACC function in bipolar patients have not differentiated subregions within this area, nor have they examined changes in these subregions in relation with DLPFC activation. METHODS: To help clarify the specific roles of these regions in bipolar patients, we examined stable patients and control subjects during performance of the Stroop test using BOLD fMRI techniques. We hypothesized that bipolar patients would demonstrate reduced activation of two subdivisions of the ACC (AAA and VOA), as well as altered activation of the DLPFC, during the interference condition. RESULTS: Results indicate that relative to controls, bipolar patients demonstrated significantly reduced signal intensity within the right AAA subdivision (p=0.011), which accompanied an increase in the DLPFC (p=0.049) during the task. LIMITATIONS: The study sample was somewhat small (11 patients, 10 controls) which limits the generalizability of the study findings, however, the patient sample consisted of well-diagnosed, stable, chronic individuals with bipolar disorder and the sample size provided enough power to detect between-group differences. CONCLUSIONS: These findings suggest differential processing strategies of bipolar patients and support the theory of altered frontal systems in these patients during the performance of cognitive tasks.     

The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia

OBJECTIVE: To compare patterns of brain atrophy in fronto-temporal dementia (FTD) and Alzheimer's disease (AD) since atrophy in individual areas may not be sufficiently specific as diagnostic marker. METHODS: Frontal, temporal and hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27 controls. Corrected atrophy and asymmetry were computed (W-scores). RESULTS: FTD had mild atrophy in the hippocampus (average W-score=-1.3), severe in the frontal (W-score=-2.4) and very severe in the temporal lobes (W-score=-2.9). AD had moderate atrophy in the hippocampus and temporal lobes (W-score=-1.8 and -1.9, respectively), and very mild frontal atrophy (W-score=-0.9). Atrophy was more asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the temporal lobes. A discriminant function including the asymmetry values of frontal and temporal regions could separate FTD from AD with 90% sensitivity and 93% specificity. CONCLUSIONS: FTD is characterized by a specific pattern of atrophy, more useful than atrophy of single regions in the differential diagnosis.     

Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA

Parent-of-origin effect in transmission of bipolar disorder and abnormal phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) findings in the brain in patients with bipolar disorder implicate pathophysiological role of mitochondrial DNA in bipolar disorder. The authors examined possible association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Genotype frequencies of the 5178 polymorphism were examined by polymerase chain reaction-restriction fragment length polymorphism method in 145 patients with bipolar disorder and 184 controls. The rate of 5178C genotype was significantly higher in patients with bipolar disorder (81/125 (64.8%), P < 0.05) compared with controls (98/184 (53.2%)) when paternally transmitted cases were excluded. This effect was more prominent in patients with bipolar II disorder (5178C: 28/37, 75.6%, P < 0.02 to controls). Bipolar II patients with 5178A genotype without family history had significantly later age at onset (56.0 +/- 14.7 years, P < 0.05) than other bipolar patients. Brain intracellular pH measured by (31)P-MRS was significantly higher in bipolar patients with 5178A (7.04 +/- 0.03, n = 7, P < 0.05) than those with 5178C (7.00 +/- 0.03, n = 7). There was no difference of subcortical hyperintensity scores by magnetic resonance imaging between patients with 5178A and those with 5178C. These results suggest that the 5178 polymorphism in mitochondrial DNA may regulate vulnerability to bipolar disorder via alteration of brain energy metabolism. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:182-186, 2000.     

Olanzapine in the treatment of adolescent acute mania: a report of seven cases.

BACKGROUND: Clozapine may be effective in adults and adolescents with treatment-resistant bipolar disorder. Olanzapine has a receptor affinity profile similar to that of clozapine. METHODS: The responses of seven consecutive adolescents (ages 12-17) with DSM-IV bipolar disorder, manic episode, treated with olanzapine were evaluated. Response to olanzapine was rated as marked, moderate, minimal, none or worse. RESULTS: Five (71%) adolescents showed a marked or moderate response. The mean+/-SD olanzapine dose was 0.146+/-0.086 mg/kg/day (11+/-6 mg/day). CONCLUSION: Olanzapine may have antimanic effects in some adolescents with acute mania. Controlled studies of olanzapine in adolescent bipolar disorder appear to be warranted.     

Medial temporal lobe abnormalities in pediatric unipolar depression

In vivo anatomical magnetic resonance imaging (MRI) studies in adults with major depressive disorder (MDD) have implicated neurocircuitries involved in mood regulation in the pathophysiology of mood disorders. Specifically, abnormalities in the medial temporal lobe structures have been reported. This study examined a sample of children and adolescents with major depressive disorder to investigate anatomical abnormalities in these key medial temporal brain regions. Nineteen children and adolescents with DSM-IV major depression (mean age +/- S.D.=13.0 +/- 2.4 years; 10 unmedicated) and 24 healthy comparison subjects (mean age +/- S.D.=13.9 +/- 2.9 years) were studied using a 1.5T Philips MRI scanner. We measured hippocampus and amygdala gray matter volumes. MRI structural volumes were compared using analysis of covariance with age and total brain volumes as covariates. Pediatric depressed patients had significantly smaller left hippocampal gray matter volumes compared to healthy controls (1.89 +/- 0.16 cm(3) versus 1.99 +/- 0.18 cm(3), respectively; F=5.0, d.f.=1/39, p=0.03; effect size: eta2(p) =0.11). Unmedicated depressed patients showed a trend towards smaller left hippocampal volumes compared to medicated patients and healthy subjects (F=2.8, d.f.=2/38, p=0.07; effect size: eta2(p) =0.13). There were no statistically significant differences in mean volumes for left or right amygdala. Smaller left hippocampal volumes in children and adolescents with MDD are in agreement with findings from adult studies and suggest that such abnormalities are present early in the course of the illness. Amygdala volumes are not abnormal in this age group. Smaller hippocampal volumes may be related to an abnormal developmental process or HPA axis dysfunction.     

Suicide attempts amongst elderly bipolar patients

BACKGROUND: Bipolar disorder is associated with high risk of suicide. In the elderly suicide rates are the highest of all age groups. There is a paucity of data regarding suicide amongst elderly bipolar patients. Mood stabilizers and particularly lithium are established as "antisuicide" compounds. OBJECTIVE: We aimed to evaluate the association between exposure to psychotropic drugs and suicide attempts in a cohort of elderly patients suffering from bipolar affective disorder (BAD). METHOD: This was a preliminary, retrospective, matched, case-controlled evaluation over a 10-year period. All records of admissions of patients with BAD (ICD-10) were assessed. The index group comprised all patients who had attempted suicide in the month prior to admission. The control group consisted of the next admission of a patient suffering from BAD, matched for sex and age who had not attempted suicide in the month prior to admission. RESULTS: The index group during the period 1995 to 2004 consisted of 16 patients, (8 men and 8 women.), mean age 74.8 +/- 1.3 years. The control group patients (N = 16) were matched for age (mean 74.3 +/- 1.5 years) and sex. The number of patients who had a history of a suicide attempt was significantly greater in the index group (7/16 vs., 2/16; p = 0.039). In the control group patients treated by both a mood stabilizer and an antidepressant were at a significantly lower risk for recent suicide attempt (p = 0.047). LIMITATIONS: Sample size is small, treatments were not standardized and data were collected retrospectively. CONCLUSION: Elderly BAD patients treated with mood stabilizers and antidepressants may be at reduced risk of attempting suicide. These findings need support from prospective randomized trials.     

The Bipolar Comprehensive Outcomes Study (BCOS): baseline findings of an Australian cohort study

BACKGROUND: The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, observational study of participants with bipolar I or schizoaffective disorder examining clinical, functional, and economic outcomes associated with naturalistic treatment. METHODS: Participants prescribed mood stabilisers were assessed using various measures, including the Young Mania Rating Scale (YMRS), 21-item Hamilton Depression Rating scale (HAMD21), Clinical Global Impressions-Bipolar Version Severity of Illness scale (CGI-BP), and the EuroQol instrument (EQ-5D). RESULTS: 240 participants were recruited from two sites. On average, participants were 41.8+/-12.7 years of age (mean+/-SD), 58.3% were female, and 73.3% had a diagnosis of bipolar I disorder at study entry. The majority of participants were moderately ill, with an average CGI-BP Overall score of 3.8+/-1.3. Most participants had subthreshold mania and depression symptoms, indicated by HAMD21 Total 13.4+/-8.6, CGI-BP Depression 3.2+/-1.3, YMRS Total 8.2+/-8.5 and CGI-BP Mania 3.0+/-1.6 average scores. For bipolar participants, 94.6% of hospitalisations for psychiatric treatment in the past 3 months were single admissions (vs. 65.2% for schizoaffective participants, p=.002). Bipolar participants rated their overall health state higher (EQ-5D scores: 68.2+/-18.8 vs. 61.6+/-22.7, p=.023), had a higher mean weekly wage ($500-$999, 21.3% vs. 6.3%), lower unemployment (22.2% vs. 48.4%), and higher romantic relationship status (47.1% vs. 26.6%). LIMITATIONS: The observational design and small sample size may have limited the causal relationships and generalisability within the current findings. CONCLUSIONS: Participants were characterised by social and occupational dysfunction at entry, but schizoaffective participants appeared to be more severely affected. Effective treatment is required to address both clinical and functional impairment.     

Structural brain correlates of IQ changes in bipolar disorder

BACKGROUND: There is increasing evidence that cognitive deficits are present in bipolar disorder (BP), but their neural correlates have not been fully explored. The aim of this study is to correlate structural brain abnormalities with cognitive performance in BP and to explore differences between clinical subtypes. METHOD: Thirty-six BP patients (13 men, 23 women) with a mean age of 39 years (range 21-63 years) underwent neuropsychological testing and imaging. Twenty-five patients had bipolar disorder I (BP I) and 11 had bipolar disorder II (BP II). Patients with co-morbid psychiatric diagnosis, drug and alcohol abuse or systemic illness were excluded. Correlations between cognitive performance and structural brain changes were explored using high-resolution anatomical imaging and magnetization transfer imaging (MTI). RESULTS: In the whole BP group the difference between estimated pre-morbid IQ and current IQ was significantly correlated with left-sided reduction of the magnetization transfer ratio (MTR) in the superior temporal gyrus, uncus and para-hippocampal gyrus. In BP II patients the areas where these correlations were significant extended to the right superior and middle temporal gyri, cingulate gyrus, pre-cuneus and adjacent frontal and parietal white matter. The volume of superior temporal white matter was also correlated with IQ difference in this subgroup. CONCLUSIONS: The study highlights the association between fronto-temporal abnormalities and decline in IQ in BP. The more extensive abnormalities present in BP II patients suggest that persistent depression, rather than mania, may be a key pathophysiological factor or that BP II represents a clinical phenotype with a higher risk of developing cognitive abnormalities.     

Antidepressant monotherapy in pre-bipolar depression; predictive value and inherent risk

OBJECTIVE: To identify specific treatment-emergent symptoms in response to antidepressant therapy in depression preceding bipolar disorder. METHODS: Retrospective chart review of response to antidepressants in "pre-bipolar" depression, compared to a matched unipolar sample. RESULTS: Family history of completed suicide (p=0.0003) and bipolar disorder (p=0.004) were more common in the pre-bipolar subgroup. Earlier age of onset of diagnosed depression (p=0.005) as well as even earlier episodes of untreated retrospectively diagnosed major depression (p<0.0001) were associated with a future bipolar course. The pre-bipolar group was less likely to respond to antidepressant treatment (p=0.009). Treatment-emergent "mixed" symptoms (two or more symptoms of DSM IV mania, mood lability, irritability/rage with co-existing depression) and in particular, "serious symptoms" (treatment emergent or increased agitation, rage or suicidality) occurred more commonly in the bipolar group. The two variables that best accounted for the between-group differences in logistic regression, were early age at first symptoms of depression and treatment-emergent agitation. CONCLUSIONS: Family history of completed suicide and/or bipolar disorder, early onset of depressive symptoms as well as treatment-emergent "mixed" symptoms are common in depression preceding the diagnosis of bipolar disorder.     

A brain MRI study in subjects with borderline personality disorder

Background: There have been only a few brain computed tomography imaging studies, with mostly negative findings, in subjects with borderline personality disorder (BPD). This is the first MRI study which evaluated the structural abnormalities of the brain in subjects with the sole diagnosis of BPD. Methods: Twenty-five subjects with BPD were compared with age-, gender-matched healthy comparison subjects (n=25) on volumes of the frontal lobes, the temporal lobes, the lateral ventricles, and the cerebral hemispheres in brain magnetic resonance imaging. Results: Subjects with BPD had a significantly smaller frontal lobe compared to comparison subjects (multivariate regression analysis, t=2.225, df=46, P=0.031). There were no significant differences in volumes of the temporal lobes, the lateral ventricles, and the cerebral hemispheres between subjects with and without BPD. Limitations: Strict inclusion and exclusion criteria employed in the present study may make it difficult to generalize our findings. The gray matter and white matter of the brain were not measured separately. Differences in head tilt during image acquisition were not corrected. Conclusions: The current study reports a smaller frontal lobe volume on brain MRI in subjects with BPD compared with healthy comparison subjects. This finding may serve as a potentially useful biological variable that may allow for subtyping BPD.     

Venlafaxine monotherapy in women with bipolar II and unipolar major depression

BACKGROUND: Women with bipolar (BP) disorder have more depressive episodes and drug-induced manic switches compared to men. Current guidelines suggest treating BP type I and type II major depressive episode (MDE) with both a mood-stabilizer and antidepressant. In a post hoc analysis, we examined the safety and efficacy of venlafaxine monotherapy in women with BP II MDE. METHODS: 15 women with BP II MDE (mean+/-SD age: 37+/-12 years) were compared to 17 women with unipolar (UP) MDE (41+/-12 years). Patients were randomized to double-blind treatment with once versus twice daily venlafaxine up to 225 mg for 6 weeks. Efficacy was measured using the HAM-D(21), MADRS and CGI scales. Drug-induced manic switch episodes characterized by agitation, irritability, euphoria or mood lability were assessed at each visit. RESULTS: No episodes of drug-induced hypomania or rapid cycling were observed during 6 weeks of venlafaxine monotherapy. Similar efficacy was observed in BP and UP depressed women (p=ns). LIMITATIONS: This study was retrospective in nature and limited in patient number. Only BP II women were included in this study, and it is possible that efficacy and the manic switch rate might have differed if BP I women were included. CONCLUSION: Short-term venlafaxine monotherapy may be a safe and effective antidepressant treatment in women with BP II MDE.     

Psychotic symptoms in patients with bipolar mania

BACKGROUND: Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. METHODS: Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. RESULTS: Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (+/-SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5+/-1.4), delusions (4.4+/-1.4), lack of judgment/insight (4.1+/-1.5), excitement (3.9+/-1.3), suspiciousness/persecution (3.1+/-1.6), and hostility (3.1+/-1.5). Grandiosity symptoms of delusional proportions (scores > or = 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. LIMITATIONS: The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. CONCLUSIONS: These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients.     

Lamotrigine for the treatment of bipolar disorder: a clinical case series.

BACKGROUND: Recently, a number of new agents have become available to treat bipolar disorder, however many patients may not respond fully even when used in combination. Early reports in epilepsy studies suggested mood-related effects of lamotrigine treatment, as have preliminary reports in bipolar patients. METHODS: Seventeen patients meeting DSM-IV criteria for bipolar I (n = 9) or bipolar II (n = 8) disorder displaying affective symptoms and a past history of inadequate response or tolerability to at least two standard mood stabilizing agents were recruited through the Stanley Foundation Bipolar Network and treated with the new anticonvulsant lamotrigine in an add-on, open-label study. Response to therapy was assessed using the Clinical Global Impression Scale modified for bipolar disorder. RESULTS: The mean dose of lamotrigine was 187+/-157 mg/day (range 50-600 mg/day) for a mean duration of 159+/-109 days (range 14-455 days). Eleven (65%) patients were rated as very much or much improved. Lamotrigine was well tolerated, and may have mood stabilizing and antidepressant properties in some patients with bipolar disorder. LIMITATIONS: The study is hypothesis generating because it was uncontrolled and open. Controlled studies are warranted. CONCLUSIONS: This preliminary report supports clinical improvement for both mood cycling and depression in patients with bipolar disorder treated with lamotrigine.