Lower Switch Rate in Depressed Patients With Bipolar II Than Bipolar I Disorder Treated Adjunctively With Second-Generation Antidepressants.

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. Methods: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score ≥3 (mildly ill). Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.Reprinted from Am J Psychiatry 2006; 163:313-315, with permission from American Psychiatric Association Publishing. Copyright © 2006.

Are personality disorders in bipolar patients more frequent in the US than Europe?

OBJECTIVE: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as "Europe") have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs). METHODS: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors. RESULTS: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe. CONCLUSIONS: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study.

Relationship of comorbid personality disorders to prospective outcome in bipolar disorder.

Introduction There is a high incidence of Axis II personality disorders (PDs) in patients with bipolar illness, but their influence on the prospectively measured course of bipolar disorder has been less well explicated. Methods 392 outpatients with bipolar disorder gave informed consent, completed the PDQ4 99 item personality disorder rating, and where clinically rated during at least one year of prospective naturalistic treatment. They were classified as Well on admission (N = 64) or Responders (N = 146) or Non-responders (N = 182) to treatment for at least six months. Results Patients who were positive for PDs were very infrequently represented in the category of Well on admission. In addition, patients with borderline, depressive, and schizoid PDs were significantly more likely to be Non-responders compared to Responders upon prospective naturalistic treatment in the network. Conclusions Patients with bipolar disorder and comorbid PDs were in general less likely to be Well from treatment in the community at network entry or to be a Responder to prospective treatment in the network. Therapeutic approaches to patients with PDs deserve specific study in an attempt to achieve a better long-term course of bipolar disorder.

Lower Switch Rate in Depressed Patients With Bipolar II Than Bipolar I Disorder Treated Adjunctively With Second-Generation Antidepressants.

(Reprinted with permission from Am J Psychiatry 2006; 163:313-315).

Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder.

INTRODUCTION: Instead of the typical assessment of risk of illness in the offspring based on a parent with bipolar disorder, we explored the potential multigenerational conveyance across several disorders of the vulnerability to illness in the offspring of a patient with bipolar disorder. METHODS: A total of 968 outpatients (average age 41 years) with bipolar illness gave informed consent and filled out a detailed questionnaire about a family history in their parents, grandparents, and offspring of: depression; bipolar disorder; alcohol abuse; substance abuse; suicide attempt; or "other" illness. Of those with children, 346 were from the USA and 132 were from Europe. Amount and type of illness in progenitors in two and three previous generations were related to offspring illness. RESULTS: The type of illness seen in both prior generations was associated with the same type of illness in the offspring of a bipolar patient, including depression, bipolar disorder, alcohol and substance abuse and "other" illness, but not suicide attempts. There was an impact of multiple generations, such that depression in grandparents and/or great-grandparents increased the risk of depression in the offspring from 12.6% to 41.4%. CONCLUSIONS: A family history of illness burden in prior generations was previously related to an earlier age of onset of bipolar illness in our adult patients with bipolar disorder and is now also found to be related to the incidence of multiple psychiatric illnesses in their offspring. Genetic and epigenetic mechanisms deserve consideration for this multigenerational conveyance of illness vulnerability, and clinical and public health attempts to prevent or slow this transmission are indicated.

Prevalence of axis II comorbidities in bipolar disorder: relationship to mood state.

OBJECTIVES: A high incidence of Axis II personality disorders is described in patients with bipolar disorder; however, their relationship to mood state remains uncertain. METHODS: A total of 966 outpatients with bipolar disorder gave informed consent and filled out the Personality Disorder Questionnaire, 4th edition (PDQ4) and a questionnaire on demographics and course of illness prior to Bipolar Treatment Outcome Network entry at average age 41 years. Patients were rated at each visit for depression on the Inventory of Depressive Symptoms-Clinician version (IDS-C) and for mania on the Young Mania Rating Scale (YMRS). In a subgroup, the PDQ4 was retaken during periods of depression and euthymia. RESULTS: Patients met criteria for most personality disorders at a much higher rate when they took the PDQ4 while depressed compared to while euthymic, and scores were significantly related to the severity of depression (IDS) and of mania (YMRS) assessed within 2 weeks of taking the PDQ. Even when euthymic, more than quarter to half of the patients met criteria for a cluster A, B or C personality disorder. CONCLUSIONS: A wide range of personality disorders occur in bipolar patients, but are highly dependent on filling out the form while depressed compared to while euthymic. How this relates to having a personality disorder assessed using a structured clinical interview remains to be tested. However, higher PDQ4 scores are related to an earlier age of onset of bipolar disorder and other factors portending a more difficult course of bipolar disorder, and the optimal treatment of these patients remains to be illuminated.

The relationship between self-reported borderline personality features and prospective illness course in bipolar disorder.

BACKGROUND: Although bipolar disorder (BD) and borderline personality disorder (BPD) share clinical characteristics and frequently co-occur, their interrelationship is controversial. Especially, the differentiation of rapid cycling BD and BPD can be troublesome. This study investigates the relationship between borderline personality features (BPF) and prospective illness course in patients with BD, and explores the effects of current mood state on self-reported BPF profiles. METHODS: The study included 375 patients who participated in the former Stanley Foundation Bipolar Network. All patients met DSM-IV criteria for bipolar-I disorder (n = 294), bipolar-II disorder (n = 72) or bipolar disorder NOS (n = 9). BPF were assessed with the self-rated Personality Diagnostic Questionnaire. Illness course was based on 1-year clinician rated prospective daily mood ratings with the life chart methodology. Regression analyses were used to estimate the relationships among these variables. RESULTS: Although correlations were weak, results showed that having more BPF at baseline is associated with a higher episode frequency during subsequent 1-year follow-up. Of the nine BPF, affective instability, impulsivity, and self-mutilation/suicidality showed a relationship to full-duration as well as brief episode frequency. In contrast all other BPF were not related to episode frequency. CONCLUSIONS: Having more BPF was associated with an unfavorable illness course of BD. Affective instability, impulsivity, and self-mutilation/suicidality are associated with both rapid cycling BD and BPD. Still, many core features of BPD show no relationship to rapid cycling BD and can help in the differential diagnosis.

More childhood onset bipolar disorder in the United States than Canada or Europe: Implications for treatment and prevention.

Evidence of a high or increasing incidence of childhood onset bipolar disorder in the United States (US) has been viewed skeptically. Here we review evidence that childhood onsets of bipolar disorder are more common in the US than in Europe, treatment delays are longer, and illness course is more adverse and difficult. Epidemiological data and studies of offspring at high risk also support these findings. In our cohort of outpatients with bipolar disorder, two of the major vulnerability factors for early onset - genetics and environmental adversity in childhood - were also greater in the US than in Europe. An increased familial loading for multiple psychiatric disorders was apparent in 4 generations of the family members of the patients from the US, and that familial burden was linked to early onset bipolar disorder. Since both early onset and treatment delay are risk factors for a poor outcome in adulthood, new clinical, research, and public health initiatives are needed to begin to address and ameliorate this ongoing and potentially devastating clinical situation.

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.

Further Evidence of a Cohort Effect in Bipolar Disorder: More Early Onsets and Family History of Psychiatric Illness in More Recent Epochs.

OBJECTIVE: Given that a cohort effect is rarely mentioned as one of the possible contributors to the increased incidence of childhood-onset bipolar disorder in the United States, we reexamined evidence for the phenomenon within our outpatient Bipolar Collaborative Network. METHODS: 968 outpatients (mean age, 41 years) with DSM bipolar disorder from 1995 to 2002 from 4 sites in the United States and 3 in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic, illness, and family history information on a patient questionnaire. Family history of bipolar disorder, depression, suicide attempt, alcohol abuse, substance abuse, and "other" illness was collected for each parent and the 4 grandparents. Age at onset and family history of illness burden were then assessed as a function of the age of the patient at network entry. RESULTS: Data for patients aged 35 years or older (n = 613) were included in the first analysis. Compared to older patients, those who were younger when they entered the network had an earlier age at onset of their bipolar disorder (r = 0.33, P < .001). Similarly, the youngest patients at entry (representing the most recent cohorts) had parents and grandparents with more psychiatric illness than patients born in earlier cohorts (n = 968). CONCLUSIONS: These preliminary data, taken with the substantial literature, suggest a cohort effect for earlier age at onset of bipolar disorder and greater burden of psychiatric disorders in 2 generations of direct progenitors of our patients. The resulting likely increase in severity of bipolar illness in future generations based on this earlier age at onset and increased familial loading, particularly in the United States, deserves focused clinical and public health attention and attempts at amelioration.

Age of onset of bipolar disorder: Combined effect of childhood adversity and familial loading of psychiatric disorders.

BACKGROUND: Family history and adversity in childhood are two replicated risk factors for early onset bipolar disorder. However, their combined impact has not been adequately studied. METHODS: Based on questionnaire data from 968 outpatients with bipolar disorder who gave informed consent, the relationship and interaction of: 1) parental and grandparental total burden of psychiatric illness; and 2) the degree of adversity the patient experienced in childhood on their age of onset of bipolar disorder was examined with multiple regression and illustrated with a heat map. RESULTS: The familial loading and child adversity vulnerability factors were significantly related to age of onset of bipolar and their combined effect was even larger. A heat map showed that at the extremes (none of each factor vs high amounts of both) the average age of onset differed by almost 20 years (mean = 25.8 vs 5.9 years of age). LIMITATIONS: The data were not based on interviews of family members and came from unverified answers on a patient questionnaire. CONCLUSIONS: Family loading for psychiatric illness and adversity in childhood combine to have a very large influence on age of onset of bipolar disorder. These variables should be considered in assessment of risk for illness onset in different populations, the need for early intervention, and in the design of studies of primary and secondary prevention.

Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up in the Stanley Bipolar Network.

OBJECTIVE: DSM-5 introduced the "with mixed features" specifier for major depressive episodes. The authors assessed the prevalence and phenomenology of mixed depression among bipolar disorder patients and qualitatively compared a range of diagnostic thresholds for mixed depression. METHOD: In a naturalistic study, 907 adult outpatients with bipolar disorder participating in the Stanley Foundation Bipolar Network were followed longitudinally across 14,310 visits from 1995 to 2002. The Inventory of Depressive Symptomatology-Clinician-Rated Version (IDS-C) and the Young Mania Rating Scale (YMRS) were administered at each visit. RESULTS: Mixed depression, defined as an IDS-C score ≥15 and a YMRS score >2 and <12 at the same visit, was observed in 2,139 visits (14.9% of total visits, and 43.5% of visits with depression) by 584 patients (64.4% of all patients). Women were significantly more likely than men to experience subthreshold hypomania during visits with depression (40.7% compared with 34.4%). Patients with one or more mixed depression visits had more symptomatic visits and fewer euthymic visits compared with those with no mixed depression visits. DSM-5-based definitions of mixed depression (ranging from narrower definitions requiring ≥3 nonoverlapping YMRS items concurrent with an IDS-C score ≥15, to broader definitions requiring ≥2 nonoverlapping YMRS items) yielded lower mixed depression prevalence rates (6.3% and 10.8% of visits, respectively) but were found to have similar relationships to gender and longitudinal symptom severity. CONCLUSIONS: Among outpatients with bipolar disorder, concurrent hypomanic symptoms observed during visits with depression were common, particularly in women. The DSM-5 diagnostic criteria for depression with mixed features may yield inadequate sensitivity to detect patients with mixed depression.

Clinical correlates of sustained response to individual drugs used in naturalistic treatment of patients with bipolar disorder.

OBJECTIVE: To report use and treatment success rates of medications for bipolar disorder as a function of patients' clinical characteristics. METHOD: Outpatients with bipolar illness diagnosed by SCID were rated by research assistants on the NIMH-LCM and those who had an good response for at least 6months (much or very much improved on the CGI-BP) were considered responders (treatment "success"). Clinical characteristics associated with treatment response in the literature were examined for how often a drug was in a successful regimen when a given characteristic was either present or absent. RESULTS: Lithium was less successful in those with histories of rapid cycling, substance abuse, or (surprisingly) a positive parental history of mood disorders. Valproate was less successful in those with ≥20 prior episodes. Lamotrigine (LTG) was less successful in those with a parental history of mood disorders or in BP-I compared to BP-II disorder. Antidepressants (ADs) had low success rates, especially in those with a history of anxiety disorders. Benzodiazepines had low success rates in those with child abuse, substance use, or ≥20 episodes. Atypical antipsychotics were less successful in the presence of rapid cycling, ≥20 prior episodes, or a greater number of poor prognosis factors. CONCLUSION: Success rates reflect medications used in combination with an average of two other drugs during naturalistic treatment and thus should be considered exploratory. However, the low long-term success rates of drugs (even when used in combination with others) that occurred in the presence of many very common clinical characteristics of bipolar illness speak to the need for the development of alternative treatment strategies.

More illness in offspring of bipolar patients from the U.S. compared to Europe.

BACKGROUND: Evidence suggests that patients with bipolar disorder from the United States have an earlier age of onset and a more difficult course of illness than those from Germany and the Netherlands. These characteristics were related to a greater family burden of psychiatric illness and the experience of more psychosocial adversity in childhood. We hypothesized that this greater illness burden would extend to the offspring of the US patients. METHODS: 968 outpatients (average age 41) with bipolar illness gave informed consent for participation in a treatment outcome network and filled out a detailed questionnaire about their illness and family history of illness, including whether their offspring had a diagnosis of depression, bipolar disorder, alcohol or substance abuse, suicide attempt or "other" illness. Of those with children, 356 were from the US and 132 were from Europe. RESULTS: Compared to the Europeans, offspring of patients from the US had significantly (p<0.001) more depression, bipolar disorder, drug abuse, and "other" illnesses. The number of illnesses in the offspring was related to the bipolar parent being from the US, having had childhood adversity, more than 20 prior episodes, and more parental psychiatric illness. CONCLUSIONS: While the findings are limited by their basis on self report, the distribution of the percentages in the US offspring are similar to those of Axelson et al. (2015) who used direct interviews. The higher burden of illness in the offspring and their in direct progenitors from the US compared to Europe warrant new attempts at better treatment and prevention.

Multigenerational Positive Family History of Psychiatric Disorders Is Associated With a Poor Prognosis in Bipolar Disorder.

The authors assessed how family history loading affected the course of illness in patients from the United States. A total of 676 outpatients with bipolar disorder from the United States rated their illness and provided a parental and grandparental history of mood disorder, substance abuse, and other clinical conditions. A positive family history for each illness was associated with almost all of the seven poor prognosis factors established in the study (abuse in childhood, early onset, anxiety and substance abuse comorbidity, rapid cycling, multiple episodes, and worsening of severity or frequency of episodes). Family history for psychiatric difficulties in parents and grandparents was associated with a more complex and difficult course of bipolar illness.

Increases in multiple psychiatric disorders in parents and grandparents of patients with bipolar disorder from the USA compared with The Netherlands and Germany.

OBJECTIVE: We previously found that compared with Europe more parents of the USA patients were positive for a mood disorder, and that this was associated with early onset bipolar disorder. Here we examine family history of psychiatric illness in more detail across several generations. METHODS: A total of 968 outpatients (average age 41) with bipolar disorder from four sites in the USA and three in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic and family history information on a patient questionnaire. Family history of psychiatric illness (bipolar disorder, unipolar depression, suicide attempt, alcohol abuse, substance abuse, and other illness) was collected for each parent, four grandparents, siblings, and children. RESULTS: Parents of the probands with bipolar disorder from the USA compared with Europe had a significantly higher incidence of both unipolar and bipolar mood disorders, as well as each of the other psychiatric conditions listed above. With a few exceptions, this burden of psychiatric disorders was also significantly greater in the grandparents, siblings, and children of the USA versus European patients. CONCLUSION: The increased complexity of psychiatric illness and its occurrence over several generations in the families of patients with bipolar disorder from the USA versus Europe could be contributing to the higher incidence of childhood onsets and greater virulence of illness in the USA compared with Europe. These data are convergent with others suggesting increased both genetic and environmental risk in the USA, but require replication in epidemiologically-derived populations with data based on interviews of the family members.

Relationship of clinical course of illness variables to medical comorbidities in 900 adult outpatients with bipolar disorder.

BACKGROUND: Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated. METHODS: The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression. RESULTS: When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship. CONCLUSION: A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated.

Verbal abuse, like physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder.

OBJECTIVES: Physical or sexual abuse in childhood is known to have an adverse effect on the course of bipolar disorder, but the impact of verbal abuse has not been well elucidated. METHODS: We examined the occurrence and frequency (never to frequently) of each type of abuse in childhood in 634 US adult outpatients (average age 40 years). Patients gave informed consent and provided information about their age of onset and course of illness prior to study entry. RESULTS: Verbal abuse alone occurred in 24% of the patients. Similar to a history of physical or sexual abuse, a history of verbal abuse was related to an earlier age of onset of bipolar disorder and other poor prognosis characteristics, including anxiety and substance abuse comorbidity, rapid cycling, and a deteriorating illness course as reflected in ratings of increasing frequency or severity of mania and depression. CONCLUSIONS: A lasting adverse impact of the experience of verbal abuse in childhood is suggested by its relationship to an earlier age of onset of bipolar disorder, other poor prognosis factors, and a deteriorating course of illness. Verbal abuse is a common confound in comparison groups defined by a lack of physical or sexual abuse. Ameliorating the impact of verbal abuse on the unfolding course of bipolar disorder appears to be an important target of therapeutics and worthy of attempts at primary and secondary prophylaxis. Family-based treatments that focus on psychoeducation, enhancing intra-family communication, and coping skills may be particularly helpful.

More medical comorbidities in patients with bipolar disorder from the United States than from the Netherlands and Germany.

Medical comorbidities are common in patients with bipolar (BP) disorder but have not been previously examined for differences between United States and Europe. More than 900 outpatients with BP I and BP II disorder (mean age, 41 years) filled out a questionnaire including the occurrence of 30 listed medical conditions. The patients from the United States were from Los Angeles, Dallas, Cincinnati, and Bethesda, whereas those from Europe were from Utrecht, Freiberg, and Munich. Those from the United States had a significantly higher incidence of obesity and nine other medical comorbidities than those from Europe, who had only more cases of hyperthyroidism. The burden of medical comorbidities in patients with BP disorder from the United States seems higher than in patients from Europe. Given the adversities, morbidity, and early mortality associated with these conditions and their interaction with the morbidity and lethality of BP disorder itself, greater efforts at treatment and prevention of these medical comorbidities would seem indicated.

Illness progression as a function of independent and accumulating poor prognosis factors in outpatients with bipolar disorder in the United States.

OBJECTIVE: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression. METHOD: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ(2), and logistical regression. RESULTS: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course. CONCLUSIONS: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder.