Familial rates of affective and substance use disorders in patients with first-episode mania

BACKGROUND: One explanation for the high co-occurrence between bipolar and substance use disorders is that substance abuse may precipitate affective symptoms in patients who otherwise may have not had the genetic risk for developing an affective illness. Previous studies comparing familial rates of affective illness between bipolar patients with and without alcohol use have provided conflicting results. We hypothesized that patients with bipolar disorder and antecedent alcohol abuse would have lower familial rates of affective illness than bipolar patients without antecedent alcohol abuse. METHODS: Family history data were obtained on 275 first-degree relatives of 51 patients hospitalized for a first manic episode using the Family History Research Diagnostic Criteria. RESULTS: Patients with bipolar disorder and antecedent alcohol abuse had lower familial rates of affective illness than patients with bipolar disorder without antecedent alcohol abuse (two-tailed Fisher's exact, P = 0.003). There was no statistically significant difference in the familial rates of affective illness between bipolar patients with and without antecedent drug abuse (other than alcohol). Patients with bipolar disorder and antecedent alcohol abuse had a significantly older age of onset of affective illness (27.6 years) than patients with bipolar disorder without antecedent alcohol abuse (20.6 years, z = 3.3, df = 1, P = 0.0009). There was no statistical difference in age of onset of affective illness between the patients with antecedent drug abuse and the patients without antecedent drug abuse. LIMITATIONS: Future studies with a larger number of bipolar patients, direct structured interviews of family members and better differentiation between substance abuse and dependence syndromes are needed to extend and replicate this pilot study. CONCLUSIONS: Our study suggests that there may be a subset of bipolar patients who have antecedent alcohol abuse and a subset who develop alcohol abuse after the onset of bipolar disorder. We further speculate that alcohol abuse may precipitate mania in some patients with bipolar disorder.     

Is treatment-associated hypomania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression

BACKGROUND: Selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) like duloxetine have the efficacy of tricyclic antidepressants (TCAs) with a more tolerable side-effect profile. Bipolar disorder is often undetected, with the most common misdiagnosis being unipolar depression. Studies have suggested that treatment of bipolar and unipolar depression with heterocyclic TCAs may increase the risk of switch rate to mania. Studies of antidepressants in unipolar major depression show a small risk of mania or hypomania, presumably because some bipolar depressives were mistakenly studied. This study investigated the rate of hypomania, mania, and hypomanic-like symptoms observed during treatment with duloxetine in patients with major depression. METHODS: This was a retrospective analysis of data from eight placebo-controlled, double-blind, randomized clinical trials of duloxetine in patients with non-bipolar major depression. LIMITATIONS: The studies were of limited duration. Manic or hypomanic symptoms were not elicited using standardized mania rating scale instruments. RESULTS: One case of mania occurred in the placebo group (0.1%), and two cases of hypomania were observed in the duloxetine-treated group (0.2%). Among hypomanic-like symptoms, only insomnia was significantly higher in the duloxetine group than in the placebo group (p<0.05). CONCLUSIONS: Duloxetine was associated with a low incidence of treatment-emergent hypomania, mania, or hypomanic-like symptoms in patients with major depressive disorder (MDD). The low incidence reported here may be due to greater diagnostic diligence on the part of the investigators. It is possible that the cases reported likely reflect inclusion of misdiagnosed bipolar II patients rather than true unipolar MDD cases. The effect of duloxetine in patients with bipolar depression is not known.     

Excess mortality of bipolar and unipolar manic-depressive patients

To compare mortality in bipolar and unipolar manic-depressive patients, 2168 manic-depressive first admissions reported to the Danish Psychiatric Central Register were divided into a bipolar group (19%), i.e., patients with at least one admission for mania during an average observation period of six years, and a unipolar group. When compared with the general population, the total group had an increased mortality by suicide and accidents in both sexes and by non-violent causes in men. The bipolar group had a higher non-violent mortality than the unipolar group, but the violent mortality was not different. Statistical problems introduced by patients switching from the unipolar to the bipolar group during the period of observation are discussed.     

Heterogeneity in EEG sleep findings in adolescent depression: unipolar versus bipolar clinical course

Background: EEG sleep measures in child and adolescent subjects with depression have shown considerable variability regarding group differences between depressed and control subjects. This investigation was designed to assess whether some of the observed variability is related to undifferentiated unipolar and bipolar disorders in a sample that was reported previously. Methods: Twenty-eight adolescents who met criteria for unipolar major depression and 35 controls with no lifetime psychiatric disorder participated in a cross-sectional sleep polysomnography study. Approximately 7 years later, follow-up clinical evaluations were conducted in 94% of the original cohort. Clinical course during the interval period was assessed without knowledge of subjects’ initial diagnostic and psychobiological status. Re-analysis of the original sleep data were performed with the added information of longitudinal clinical course. Results: Depressed subjects who had a unipolar course showed reduced REM latency, higher REM density, and more REM sleep (specifically in the early part of the night) compared with depressed adolescents who converted to bipolar disorder and controls who remained free from psychopathology at follow-up. In contrast to the unipolar group, depressed subjects who would later switch to bipolar disorder had demonstrated more stage 1 sleep and diminished stage 4 sleep. Conclusions: These preliminary results indicate that some of the observed variability in EEG sleep measures in adolescent depression appear to be confounded by latent bipolar illness. The findings also suggest that sleep regulatory changes associated with unipolar versus bipolar mood disorders may be different.     

The premorbid personality of patients with different subtypes of an affective illness. Statistical analysis of blind assignment of case history data to clinical diagnoses

On the basis of case history data, the assumption that there exists an association between the 'manic type' of personality and a predominantly manic course of an affective illness, and between the 'melancholic type' of personality and a unipolar depressive course of the illness was examined. Premorbid data were extracted from 42 case records, 10 of 'unipolar' manic subjects (the ratio of manic to depressive episodes greater than or equal to 4:1), 11 of typical bipolar I patients, 11 of bipolar II patients, and 10 of unipolar endogenous depressives. A rater (J.P.), blind to diagnosis and selection procedure, assigned case notes to personality types. Differences were predicted in terms of personality type between the two unipolar groups, the two bipolar groups and, due to the higher number of cases, also between the combined groups of 'unipolar' manic and bipolar I patients on the one hand, and unipolar depressive and bipolar II patients on the other. According to the Fisher test these predictions were fulfilled. Furthermore, in agreement with our hypotheses on the relationship between premorbid personality and course of the disease, the ratio of assignments to 'manic type' and 'melancholic type' decreased from 'unipolar' mania, to bipolar I and bipolar II disorders, and to unipolar depression.     

The high prevalence of bipolar II and associated cyclothymic and hyperthymic temperaments in HIV-patients

Background: Although recent studies have shown high rates of current and lifetime depression in HIV-infected patients, there is little systematic data on the occurrence of bipolarity in these patients. Method: We compared 46 HIV patients with index major depressive episode (MDE) to an equal number of age- and sex-matched seronegative MDE patients, and systematically examined rates of DSM-III-R bipolar subtypes (enriched in accordance with Akiskal's system of classifying soft bipolar disorders). Results: Although HIV and psychiatric clinic patients had comparable background in terms of familial affective loading, HIV patients had significantly higher familial rates for alcohol and substance use. The more important finding was the significantly higher proportion of HIV patients with lifetime bipolar II disorder (78%), and associated cyclothymic (52%) and hyperthymic (35%) temperaments; the findings were the same irrespective of HIV risk status (intravenous drug user vs. homosexual and other risk groups combined). Limitations: The major methodologic limitation of our study is that clinicians evaluating temperament were not blind to affective diagnoses and family history. The comparison affective group was a sample of convenience drawn from the same tertiary care university facility. Conclusion: The finding of a high rate of bipolar II disorder in HIV patients has treatment implications for seropositive patients presenting with depression. More provocatively, we submit that premorbid impulsive risk-taking traits associated with cyclothymic and hyperthymic temperaments may have played an important role in needle-sharing drug use and/or unprotected sexual behavior, leading ultimately to infection with HIV. Given their public health importance, these clinical findings and insights merit further investigation. In particular, systematic case-control studies, as well as other large scale studies with prospective methodology need to be conducted.     

Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament.

In an attempt to improve the classification of Bipolar II disorders, we have examined a consecutive series of 687 primary major depressives: 5.1% gave a past history of mania (Bipolar I), 13.7% met our operational criteria for hypomania (Bipolar II), and the remaining 81.2% were provisionally categorized as 'unipolar.' Although Bipolar II was in some respects intermediate between Bipolar I and Unipolar, gender, familial bipolar history, age at onset and course characteristics generally supported its closer kinship to bipolar illness. Seventy one of the unipolars (10.3% of the total series) further met our operational criteria for hyperthymic temperament (U-HT), leaving behind a purer unipolar group of 487 major depressives. With respect to the proportion having male gender and bipolar family history, U-HT was similar to Bipolar I and II, and all three differed significantly from pure unipolar; as for age at onset, number of episodes and related indices of course, BI and BII were similar, and U-HT was closer to pure unipolar. These findings suggest that major depressive episodes arising from a hyperthymic temperament (constituting 12.4% of the 'unipolar' universe by conventional definition) are 'genotypically' closer to Bipolar II defined by hypomania, and course-wise similar to other unipolars.     

Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice

BACKGROUND: Fatigue is a common symptom of depression, especially the bipolar type. Modafinil is a wake-promoting agent that can alleviate fatigue in depressed patients. Many stimulants used to treat fatigue carry the risk of a switch into mania or hypomania in bipolar patients as well as the risk for tolerance or abuse. METHOD: A retrospective chart review was performed on all patients currently being seen in a large outpatient practice who received modafinil at some point during their treatment. Data collected included patient demographics, MiniSCID diagnoses, clinical diagnoses including history of substance abuse, and length and dosage of treatment with modafinil. RESULTS: Of the 191 patients who were given modafinil at some point during their treatment, 105 patients remained on it for 2 months or more and 37% of these patients were bipolar (18 BPI and 21 BPII). In addition, 86 patients were on modafinil for less than 2 months and 31% of these patients were bipolar(16% BPI and 15% BPII). No patients in any group demonstrated a switch into mania or hypomania while on modafinil. There was also no significant difference in final modafinil dosage between patients who had a positive history of chemical abuse/dependence (290 mg/day) and those who did not (258 mg/day). LIMITATIONS: Retrospective chart review. CONCLUSIONS: Adult affective disorder patients, whether unipolar or bipolar, can use modafinil to relieve symptoms of depression, including fatigue and sleepiness, without risking a switch in their mood or developing tolerance or abuse of this medication.     

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.     

Unipolar mania: a distinct disorder?

BACKGROUND: This study aimed to identify the differences between unipolar mania and classical bipolar disorder. METHODS: Patients with at least four manic episodes and at least 4 years of follow-up without any depressive episodes were classified as unipolar mania. This group was compared to other bipolar-I patients defined according to DSM-IV regarding their clinical and socio-demographic variables. RESULTS: The rate for unipolar mania as defined by the study criteria was found to be 16.3% in the whole group of bipolar-I patients. Unipolar manic patients tended to have more psychotic features and be less responsive to lithium prophylaxis compared to other bipolar-I patients. LIMITATIONS: Because it was a retrospective study, there may be some minor depressive episodes left unrecorded in the unipolar mania group despite careful and thorough investigation. In addition, even with our fairly strict criteria for the diagnosis of unipolar mania, the possibility of a future depressive episode cannot be excluded. CONCLUSIONS: Unipolar mania may be the presentation of a nosologically distinct entity.     

Sleep of atypical depressives

Patients who met provincial criteria for atypical depression were contrasted with a group of patients who met RDC criteria for endogenous depression and a group of normal controls on a standard series of sleep variables. Atypical depressives were differentiated from normal controls by a shortened REMP latency. They did not, however, appear to have the sleep continuity disturbance exhibited by endogenous depressives. This preliminary work suggests that atypical depressives may have a unique pattern of sleep variables consisting of REM abnormalities without continuity disturbance. If this pattern is observed in additional studies, it would add to the validity of considering atypical depression a subtype of unipolar depressive illness.     

The perception of emotional chimeric faces in patients with depression,mania and unilateral brain damage

BACKGROUND: Judgements made on chimeric faces elicit reliably a perceptual bias to the left hemispace, presumed to be due to right hemisphere dominance for emotional processes. Major depressive illness has been shown to attenuate this bias. The aim of this work was to examine lateral perceptual bias in bipolar I and II patients in a hypomanic state and unipolar depressed patients and those with unilateral hemisphere damage following stroke. METHOD: Sixty patients with DSM-IV affective disorder (30 bipolar I or II, currently hypomanic, 30 unipolar depressives), 30 right brain-damaged patients, 30 left brain-damaged patients and 30 healthy controls were given the Happy-Sad Chimeric Faces Test. RESULTS: Right hemisphere damaged and unipolar depressed patients both showed a significantly reduced left hemispatial bias (LHB) compared to controls, bipolars and left brain-damaged patients. No significant difference in mean LHB between controls and both hypomanics and left brain-damaged patients was found. There was no significant association between LHB and clinical variables. CONCLUSIONS: The results suggest a physiological distinction between bipolar and unipolar depression. The significantly diminished left hemifacial bias in depressed patients suggests right hemisphere dysfunction.     

Sensitivity and specificity of the Mood Disorder Questionnaire for detecting bipolar disorder

BACKGROUND: This study aims to replicate the sensitivity and specificity of the Mood Disorder Questionnaire (MDQ) for bipolar disorder and assess the impact of insight on the MDQ's sensitivity. Unlike prior telephone-based validation, this is the first clinical study to assess the validity of the MDQ. METHODS: 37 consecutive patients with bipolar spectrum illness received the MDQ, as well as 36 consecutive patients with unipolar depression. MDQ diagnoses were compared to DSM-IV-based SCID diagnoses. A total of 16 bipolar patients also received the Scale to Assess Unawareness of Mental Disorder (SUMD) to measure insight. RESULTS: Overall sensitivity for the MDQ was 0.58, higher in bipolar I disorder (0.69) than in bipolar II/NOS (0.30, P=0.06). The sample was highly insightful, but the two patients with lowest insight both had false negative screens. Patients' low ratings of severity of mania (question 3 of the MDQ) explained almost half of all false negative results. Specificity was 0.67. CONCLUSIONS: The MDQ demonstrates good sensitivity in insightful patients with bipolar I disorder, but may be less useful in patients with impaired insight or milder bipolar spectrum conditions.     

On the increased risk of developing late-onset epilepsy for patients with major affective disorder

BACKGROUND: Based on register data we wanted to investigate whether patients with a diagnosis of affective disorder are at increased risk of developing epilepsy compared to other medically ill control groups. METHODS: By linkage of public hospital registers covering the whole of Denmark from 1977 to 1993, using ICD-8 diagnoses, three study cohorts were identified: Patients with first affective disorder episodes (mania and depression), patients with first osteoarthritis and patients with first diabetes discharge. Time to first diagnosis of epilepsy was estimated with the use of survival analysis. RESULTS: A total of 164,227 patients entered the study base: 13,748 patients with mania or depression, 81,380 patients with osteoarthritis and 69,149 patients with diabetes. The risk of getting a diagnosis of epilepsy was increased for patients with affective disorder compared with the risk for the control groups. However, the increased risk seemed to be due to the effect of comorbid alcohol or drug abuse and not to the effect of the affective illness itself. LIMITATIONS: The results only apply to hospitalised patients. Diagnoses are not validated for research purposes. CONCLUSION: Patients with a diagnosis of affective disorder have an increased risk of developing epilepsy in later life. In patients with affective disorder, comorbid alcoholism/drug abuse seriously increased the risk of a subsequent diagnosis of epilepsy.     

Social functioning and personality of subjects at familial risk for affective disorder

BACKGROUND: Particular patterns of personality (e.g., neuroticism, obsessionality) and difficulties in various social roles have been found to be associated with unipolar depression. Interpersonal and instrumental difficulties of depressives can be understood either as a risk factor, or as a consequence caused by the disorder itself. Concerning patients with bipolar disorder, there is some evidence that their premorbid level of occupational and educational achievement is often superior when compared to the premorbid functioning of patients with unipolar depression. METHODS: Personality features and the level of social functioning of 114 high-risk subjects (healthy first-degree relatives of patients suffering from an affective disorder) have been investigated using self- and expert-ratings. Sixty-three subjects without a personal and family history of psychiatric disorder served as the reference group. RESULTS: Relatives of melancholic depressives described themselves as more neurotic than controls but proved to be inconspicuous regarding their role functioning. Relatives of bipolar I patients were more strongly oriented toward social norms, and their instrumental role functioning was superior to that of controls. Neuroticism was strongly associated with depressive symptoms. LIMITATION: The statistical power of our data is sufficient to detect medium effect sizes but is insufficient for identifying small group differences. CONCLUSION: Whether these discriminating personality features and other variables (not characterising the high-risk group (HRG) as a whole) act as true vulnerability factor have to be clarified by a follow-up investigation.     

Distinctions between bipolar and unipolar depression

This is a review of the studies comparing unipolar and bipolar depression, with focus on the course, symptomatology, neurobiology, and psychosocial literatures. These are reviewed with one question in mind: does the evidence support diagnosing bipolar and unipolar depressions as the same disorder or different? The current nomenclature of bipolar and unipolar disorders has resulted in research that compares these disorders as a whole, without considering depression separately from mania within bipolar disorder. Future research should investigate two broad categories of depression and mania as separate disease processes that are highly comorbid.     

Prevalence and correlates of bipolar II disorder in major depressive patients at a psychiatric outpatient clinic in Hong Kong

BackgroundWestern studies indicate a high prevalence of bipolar II disorder defined by a Research Diagnostic Criteria 2-day hypomania duration criterion (30 to 61%) amongst clinically depressive patients. The situation in Chinese patients with depression is unknown.Methods64 (52.5% response rate) patients first presenting to a Hong Kong public psychiatric outpatient clinic in 2005 with a diagnosis of major depression were recruited. The SCID and Family History Screen were administered.ResultsDSM-IV bipolar II was found in 20.5% of depressive outpatients; 35.9% had bipolar II disorder defined by RDC 2-day duration criterion for hypomania. Family bipolarity, age of onset, and depressive recurrence distinguished bipolar II subjects from unipolar depressives irrespective of duration criteria chosen for hypomania.LimitationsSample size was limited.ConclusionsBipolar II disorder is common amongst Chinese depressive outpatients. The evaluation method and 2-day duration criterion for hypomania were supported by bipolar validators. Replication using larger samples is needed to arrive at a more representative prevalence estimate and to enable more refined nosological evaluation.     

Unipolar mania revisited.

In a more sophisticated replication of an earlier study (Abrams and Taylor 1974), we examined 77 manic patients, of whom 29 had never suffered a depressive illness, and had two or more manic attacks. These unipolar manics were similar to the 48 bipolar manics for a wide variety of clinical, phenomenological, historical, laboratory and demographic variables, generally supporting our earlier findings. However, the present sample showed a striking excess of males among the unipolar manics, as well as an increased morbid risk for unipolar depression in first-degree relatives. Although not readily explainable, these differences suggest that it is premature to equate unipolar mania with classical bipolar illness. Further studies of unipolar mania are in progress.     

A comparative study on dual patients with affective disorder

BACKGROUND: The main purpose of the study was to investigate whether there are differences between dual patients with affective disorders regarding the different kinds of substances abused - a topic which has hardly been dealt with in the literature. METHODS: Clinical charts of 94 dual and 94 non-dual patients, matched for sex, age, and diagnosis, were scrutinized and the data of both groups compared with each other, with regard to the substance of abuse. RESULTS: A total of 17.4% of all patients with affective disorders were found to be dual patients and the proportion of dual patients was equal among patients with unipolar disorder, bipolar disorder, and dysthymia. Only a few significant differences were found between dual and non-dual patients; more differences were identified when the dual group was divided into patients abusing alcohol (59%), opioids/cocaine (22%), and sedatives/hypnotics (19%). In particular, the group of patients abusing illegal drugs was found to be younger and to show more behavioral pathology. All three groups of dual patients differed regarding the onset of their affective illness. LIMITATIONS: Retrospective study of clinical records. CONCLUSIONS: There are differences between dual patients with affective disorders abusing different substances. The choice of a particular substance of abuse appears to be the function of the age of onset of the disorder.