Illnesses in siblings of US patients with bipolar disorder relate to multigenerational family history and patients severity of illness.

BACKGROUND: Patients with bipolar disorder from the US have more early-onset illness and a greater familial loading for psychiatric problems than those from the Netherlands or Germany (abbreviated here as Europe). We hypothesized that these regional differences in illness burden would extend to the patients siblings. METHODS: Outpatients with bipolar disorder gave consent for participation in a treatment outcome network and for filling out detailed questionnaires. This included a family history of unipolar depression, bipolar disorder, suicide attempt, alcohol abuse/dependence, drug abuse/dependence, and "other" illness elicited for the patients' grandparents, parents, spouses, offspring, and siblings. Problems in the siblings were examined as a function of parental and grandparental problems and the patients' adverse illness characteristics or poor prognosis factors (PPFs). RESULTS: Each problem in the siblings was significantly (p<0.001) more prevalent in those from the US than in those from Europe. In the US, problems in the parents and grandparents were almost uniformly associated with the same problems in the siblings, and sibling problems were related to the number of PPFs observed in the patients. LIMITATIONS: Family history was based on patient report. CONCLUSIONS: Increased familial loading for psychiatric problems extends through 4 generations of patients with bipolar disorder from the US compared to Europe, and appears to "breed true" into the siblings of the patients. In addition to early onset, a variety of PPFs are associated with the burden of psychiatric problems in the patients' siblings and offspring. Greater attention to the multigenerational prevalence of illness in patients from the US is indicated.

Age at Onset of Bipolar Disorder Related to Parental and Grandparental Illness Burden.

OBJECTIVE: The age at onset of bipolar disorder varies greatly in different countries and continents. The association between load of family history of psychiatric illness and age at onset has not been adequately explored. METHODS: 979 outpatients with bipolar disorder (from 4 sites in the United States and 3 in the Netherlands and Germany) gave informed consent and completed a questionnaire about their demographics, age at onset of illness, and family history of unipolar and bipolar disorder, alcohol and substance abuse comorbidity, suicide attempts, and "other" illnesses in their parents, 4 grandparents, and any offspring. We examined how the parental and grandparental burden of these illnesses related to the age at onset of the patients' bipolar disorder. RESULTS: The burden of family psychiatric history was strongly related to an earlier age at onset of illness in both US and European patients (F3,906 = 35.42, P < .0001). However, compared to the Europeans, patients in the United States had both more family history of most difficulties and notably earlier age at onset. Earlier age at onset was associated with a greater illness burden in the patient's offspring (t568 = 4.1, P < .0001). CONCLUSIONS: More parental and grandparental psychiatric illness was associated with an earlier age at onset of bipolar disorder, which is earlier in the United States compared with Europe and is strongly related to a poor long-term prognosis. This apparent polygenic contribution to early onset deserves further study and therapeutic attempts at ameliorating the transgenerational impact.

Lamotrigine in psychiatric disorders.

OBJECTIVE: Owing to the prevalence of medication side effects and treatment resistance, prescribers often consider off-label uses of US Food and Drug Administration (FDA)-approved agents for the treatment of persistent symptoms. The authors review the available literature on the FDA-approved and non-FDA-approved uses of lamotrigine in adults with psychiatric disorders. DATA SOURCES: We used PubMed, MEDLINE, and a hand search of relevant literature to find studies published between 1990 and 2012 and available in English language. The following keywords were searched: lamotrigine, psychiatric, mood disorders, depression, personality disorders, anxiety, schizophrenia, side effects, and rash. STUDY SELECTION: Data were selected from 29 randomized controlled trials (RCTs). When RCTs were not available, open-label trials (6), retrospective case reviews (10), and case series (4) were summarized. DATA EXTRACTION: We extracted results of monotherapy and augmentation trials of lamotrigine on primary and secondary outcome measures. RESULTS: Lamotrigine is generally well tolerated, with the best evidence for the maintenance treatment of bipolar disorder, particularly in prevention of depressive episodes. In acute bipolar depression, meta-analyses suggested a modest benefit, especially for more severely depressed subjects, with switch rates similar to placebo. In unipolar depression, double-blind RCTs noted benefit on subsets of symptoms and improved response in more severely depressed subjects. Data are limited but promising in borderline personality disorder. Use of lamotrigine in schizophrenia and anxiety disorders has little supportive evidence. CONCLUSIONS: Lamotrigine is recommended in bipolar maintenance when depression is prominent. It also has a role in treating acute bipolar depression and unipolar depression, though the latter warrants more research. Data are too limited in other psychiatric disorders to recommend its use at this time.

Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals.

BACKGROUND: Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers. METHODS: Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively). RESULTS: Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor. CONCLUSIONS: The R(2) and RD trajectories were most dynamic in late-myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend.

Unmet needs in bipolar depression.

Bipolar disorders, particularly bipolar spectrum disorders, frequently go unrecognized and undiagnosed by clinicians and thus remain untreated or inappropriately treated. Although the symptoms of bipolar I disorder are widely acknowledged and recognized among clinicians, epidemiology sampling studies over the past several years have found that bipolar II disorder and bipolar spectrum disorders are likely to be more prevalent and more challenging to diagnose, particularly as depressive presentations are far more common in these groups. Bipolar disorder is associated with increased morbidity and mortality, as well as higher healthcare costs, but it is unclear how much of the consequences of bipolar disorder are unrecognized in the face of poor recognition of bipolar II and bipolar spectrum disorders. This article addresses challenges in diagnosing and treating bipolar disorder in the face of a depressive episode, and offers guidelines for recognizing and appropriately managing these patients. Studies with the newer anticonvulsant mood stabilizer lamotrigine have shown antidepressant effects in bipolar disorder, and may fill an unmet need for treatment options in patients who present with depression in the context of bipolar disorder.

A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network.

OBJECTIVES: The risk-to-benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations. METHODS: In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health-Life Chart Method (NIMH-LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs. RESULTS: Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re-emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15-20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs. CONCLUSIONS: These data reveal that depression and depressive cycling remain a substantial problem in some two-thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania.

An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).

AIM AND METHODS: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. RESULTS: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. CONCLUSIONS: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.