Antecedents of manic versus other first psychotic episodes in 263 bipolar I disorder patients.

OBJECTIVE: As initial episode type can predict later morbidity in bipolar disorder, we tested the hypothesis that clinical antecedents might predict initial episode types. METHOD: We studied 263 first-episode, adult, DSM-IV-TR type I bipolar disorder (BD-I) subjects within the McLean-Harvard-International First-Episode Project. Based on blinded assessments of antecedents from SCID examinations and clinical records, we compared first lifetime manic vs. other (mixed, depressive, or non-affective) major psychotic episodes. RESULTS: We identified 32 antecedents arising at early, intermediate or later times, starting 12.3±10.7 years prior to first lifetime major psychotic episodes. Based on multivariate modeling, antecedents associated significantly and independently with other (n=113) more than manic (n=150) first lifetime major psychotic episodes ranked by odds ratio: more early attentional disturbances, more late depression, more early perplexity, more detoxification, more early unstable mixed affects, more antidepressants, more early dysphoria, more intermediate depression, more early impulsivity, more late anhedonia, longer early-to-intermediate intervals, more intermediate substance abuse, more family history of major depression, and younger at earliest antecedents. Antecedents selectively preceding manic more than other first psychotic episodes included more late behavioral problems and more risk of familial BD-I. CONCLUSION: Clinical antecedents in adult, BD-I patients, beginning a decade before first major episodes and progressing through sequential stages were dissimilar in manic vs. other first psychotic episodes.

The McLean-Harvard first-episode project: 6-month symptomatic and functional outcome in affective and nonaffective psychosis.

BACKGROUND: The McLean-Harvard First-Episode Project recruited affective and nonaffective patients at their first lifetime psychiatric hospitalization. METHODS: Baseline evaluation and 6-month follow-up in 257 cases yielded recovery outcomes defined by syndromal (absence of DSM-IV criteria for a current episode) and functional (vocational and residential status at least at baseline levels) status. Time to recovery was assessed by survival analysis, and risk factors by multivariate logistic regression. RESULTS: Syndromal recovery was attained by 77% of cases over an average of 84 days. By diagnostic group, syndromal recovery rates ranked (p = .001) major affective disorders (81%) > nonaffective acute psychoses (74%) > schizoaffective disorders (70%) > schizophrenia (36%). Functional recovery was significantly associated to syndromal recovery, diagnosis, shorter hospitalization normalized to year, and older age at onset. Average hospital stay declined across the study period, but recovery did not vary with year of entry. CONCLUSIONS: Syndromal recovery was achieved by nearly one half of patients within 3 months of a first lifetime hospitalization for a psychotic illness, but functional recovery was not achieved by 6 months in nearly two thirds of patients who had attained syndromal recovery.

Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features.

OBJECTIVE: Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders. METHOD: From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods. RESULTS: By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period. CONCLUSIONS: Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele.

Bipolar spectrum disorders are recurrent illnesses characterized by episodes of depression, hypomania, mania or the appearance of mixed states. Great variability is evident in the frequency of episode recurrence and duration. In addition to regular circannual episodes, a spectrum of cycle frequencies has been observed, from the classical rapid cycling (RC) pattern of four or more episodes per year, to those with distinct shifts of mood and activity occurring within a 24-48 h period, described as ultra-ultra rapid cycling (UURC) or ultradian cycling. RC has a female preponderance, and occurs with greater frequency premenstrually, at the puerperium and at menopause. Tricyclic antidepressants and MAOIs, both of which increase functional monoamines norepinephrine, dopamine and serotonin, are known to precipitate mania or rapid-cycling in an estimated 20-30% of affectively ill patients. We have recently reported a strong association between velo-cardio-facial syndrome (VCFS) patients diagnosed with rapid-cycling bipolar disorder, and an allele encoding the low enzyme activity catechol-O-methyltransferase variant (COMT L). Between 85-90% of VCFS patients are hemizygous for COMT. Homozygosity for the low activity allele (COMT LL) is associated with a 3-4 fold reduction of COMT enzyme activity compared with homozygotes for the high activity variant (COMT HH). There is nearly an equal distribution of L and H alleles in Caucasians. Individuals with COMT LL would be expected to have higher levels of transynaptic catecholamines due to a reduced COMT degradation of norepinephrine and dopamine. We therefore hypothesized that the frequency of COMT L would be greater in RC BPD ascertained from the general population. Significantly, we found that the frequency of COMT L was higher in the UURC variant of BPD than among all other groups studied (P = 0.002). These findings indicate that COMT L could represent a modifying gene that predisposes to ultra-ultra or ultradian cycling in patients with bipolar disorder.

Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders.

Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate, learning disabilities, and characteristic facial appearance and is associated with hemizygous deletions within 22q11. A newly recognized clinical feature is the presence of psychiatric illness in children and adults with VCFS. To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, we evaluated 26 VCFS patients by clinical and molecular biological methods. The VCFS children and adolescents were found to share a set of psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients, >18 years of age, were affected with bipolar spectrum disorders. Four of six adult patients had psychotic symptoms manifested as paranoid and grandiose delusions. Loss-of-heterozygosity analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal deletion and two did not have a detectable deletion. Somatic cell hybrids were developed from the two patients who did not have a detectable deletion within 22q11 and were analyzed with a large number of sequence tagged sites. A deletion was not detected among the two patients at a resolution of 21 kb. There was no correlation between the phenotype and the presence of the deletion within 22q11. The remarkably high prevalence of bipolar spectrum disorders, in association with the congenital anomalies of VCFS and its occurrence among nondeleted VCFS patients, suggest a common genetic etiology.

Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder?

OBJECTIVE: The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11. METHOD: Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptoms. RESULTS: Sixty-four percent (N = 16 of 25) of this unselected series of patients with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. In contrast to previous reports of a high prevalence of schizophrenia, none of the patients was diagnosed with schizophrenia, and only four had psychotic symptoms during a phase of their illness, all in their 20s or 30s. CONCLUSIONS: Given that the prevalence of bipolar disorder in the general population is estimated to be 1.5% and that the average age at onset is 24, these findings support an unusually strong association between velo-cardio-facial syndrome and early-onset bipolar disorder and suggest that a gene deleted at the 22q11 chromosomal locus may be involved in its pathogenesis. If confirmed, these findings may provide a new and fruitful line of investigation into the molecular basis of bipolar spectrum disorders.

Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders.

BACKGROUND: Gradual discontinuation of lithium may reduce high risk of early morbidity in bipolar disorder patients discontinuing successful long-term maintenance on lithium, but previous small samples have limited analyses of subgroups. METHOD: DSM-IV bipolar disorder patients (N = 161) were pooled from similar samples maintained on lithium for 4.2 +/- 3.1 years. Effects of discontinuing treatment abruptly (1-14 days) or gradually (15-30 days) were compared by survival analysis in clinically closely similar groups. RESULTS: After gradual versus rapid discontinuation, the overall median time to recurrence +/- SE differed by 5.0-fold (20.0 +/- 5.8 vs. 4.0 +/- 0.7 months; p < .0001). After rapid discontinuation, the median time in remission was 2.3 times shorter than the mean cycling interval before lithium (6.3 vs. 14.6 months; p < .0001). The proportion of subjects falling ill/month (recurrence rate) was much higher in the first year after rapid discontinuation (6.5% vs. 2.3%), but similar thereafter (0.4% vs. 0.6%); patients remained stable for 3 years when off lithium treatment 20 times more frequently after gradual than rapid discontinuation (37% vs. 1.8%; p < .0001). Ratios of median survival times after gradual/rapid lithium discontinuation were similar for a first recurrence of mania and depression (4.4 vs. 3.4-fold), insignificantly higher (34%) with rapid or continuous cycling before lithium, and greater in Type II than Type I disorder (9.8- vs. 4.0-fold). The polarity of first off-lithium and first lifetime episodes matched in 70% of cases. CONCLUSION: These pooled results strengthen the concept or a pharmacodynamic stress factor in early relapse after stopping lithium maintenance and support the conclusion that early recurrence risk can be minimized by discontinuing maintenance treatment gradually in both Type I and II bipolar disorders.

Prevalence and characteristics of physical and sexual abuse among psychiatric outpatients.

Eighty-six female and 34 male psychiatric outpatients completed a self-report questionnaire that retrospectively assessed their history of physical and sexual abuse and assault. Seventy percent reported an abusive experience in childhood or adulthood. Female subjects were more likely than male subjects to report childhood sexual abuse and adult physical and sexual assaults. For all subjects, childhood sexual abuse was associated with adult sexual and physical assault. The charts of several patients who reported abuse histories did not include any record of abuse.

Pediatric-onset bipolar disorder: a neglected clinical and public health problem.

Bipolar disorder (BPD), probably the most prevalent psychotic disorder in adults, has been relatively neglected or controversial in children and adolescents over the past century. We reviewed the literature on early-onset BPD. Estimates of prevalence, particularly before puberty, are limited by historical biases against pediatric mood disorders and by formidable diagnostic complexity and comorbidity. Although clinical features of pediatric and adult BPD have similarities, pediatric cases probably cannot be defined solely by features characteristic of adult cases. Onset was before age 20 years in at least 25% of reported BPD cases, with some increase in this incidence over the past century. Pediatric BPD is familial more often than is adult-onset BPD, may be associated with a premorbid cyclothymic or hyperthymic temperament, and can be precipitated by antidepressant treatment. Pediatric BPD episodes frequently include irritability, dysphoria, or psychotic symptoms; they are commonly chronic and carry high risks of substance abuse and suicide. BPD is often recognized in adolescents, but the syndrome or its antecedents are almost certainly underrecognized and undertreated in children. Controlled studies of short- and long-term treatment, course, and outcome in this disorder remain strikingly limited, and the syndrome urgently requires increased clinical and scientific interest.

Correlates of violence risk in hospitalized adolescents.

Forty adolescent inpatients with histories of frequent interpersonal violent behavior were compared with 36 hospitalized adolescents without histories of overt violence using self-report questionnaires that measured violence risk, depression, impulsivity, and suicide risk. The two groups did not differ in terms of their demographic characteristics, but the violent patients had a higher prevalence of substance abuse and borderline personality disorder diagnoses. Violent adolescents were more impulsive and at higher suicide risk than nonviolent adolescents. In addition, violent adolescents had more positive histories of suicide attempts and had significantly higher family histories of attempted and completed suicide. In the total sample of adolescents, violence risk was significantly correlated with impulsivity and suicide risk, but not with depression.

Discontinuation of maintenance treatment in bipolar disorder: risks and implications.

There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.

The Tridimensional Personality Questionnaire as a predictor of six-month outcome in first episode mania.

The authors administered the Tridimensional Personality Questionnaire (TPQ) near hospital discharge to 27 patients with first episode mania. All patients met DSM-III-R criteria for bipolar disorder, manic type, as assessed by the Structured Clinical Interview for DSM-III-R. Associations of TPQ scores with operationalized outcome variables were analyzed. Outcome variables included syndromic recovery at discharge and at 6 months, syndromic recurrence, and functional recovery. Patients who failed to achieve functional recovery by 6 months had significantly higher Novelty-Seeking dimensional scores at the time of hospital discharge. This association between TPQ scores and short-term outcome suggests that elevated Novelty-Seeking scores may reflect either personality characteristics that impair functional recovery or subclinical manic symptomatology that is not reflected in other symptom measures. The TPQ may provide useful prognostic measures in patients with new onset mania.

Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders.

OBJECTIVE: Withdrawal of bipolar mood disorder (BP-I) patients from prolonged, stable lithium maintenance has a high risk of early recurrence, particularly of mania. We thus compared risks of stopping lithium rapidly vs gradually. DESIGN: Outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed. PATIENTS: Subjects (N = 64) with a DSM-III-R BP disorder, previously stable on lithium monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium (elected in prolonged wellbeing in 67%). None was unavailable for follow-up, and subtyping (BP-I or BP-II) remained stable. RESULTS: Within 5 years, 75% had a recurrent episode; BP-I patients were 1.5-times less likely than BP-II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2) than gradual (2 to 4 weeks discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups. CONCLUSIONS: Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.

Comorbidity in psychosis at first hospitalization.

OBJECTIVE: The authors sought to determine the prevalence and effects of medical and psychiatric comorbidity on initial outcome in a group of patients experiencing a first episode of psychosis. METHOD: Patients with a first episode of psychosis who were consecutively admitted to a hospital (N = 102) were examined for the presence of psychiatric and medical disorders. Patients were given psychiatric diagnoses with the use of the Structured Clinical Interview for DSM-III-R and were rated weekly on symptom rating scales. Outcome variables at discharge were final symptom rating scale scores, length of hospitalization, and recovery on the basis of operationalized criteria. RESULTS: Comorbid diagnoses were present in 52.0% (N = 53) of the patients, and 37.7% (N = 20) had multiple comorbid diagnoses. The most common comorbid diagnosis was substance abuse. Patients with affected psychoses were significantly more likely than those with nonaffective psychoses to have a comorbid substance abuse diagnosis. Patients with psychiatric comorbidity had poorer initial outcomes, while those with medical comorbidity had fewer symptoms at discharge. CONCLUSIONS: Comorbidity is common and may be a useful predictor of the outcome of a first episode of psychosis.

Seasonal mood disorders. Patterns of seasonal recurrence in mania and depression.

DSM-III-R criteria, applied retrospectively in a research-oriented psychiatric clinic, identified patients (N = 146) with a mood disorder and a seasonal pattern of recurrence (seasonal mood disorder). The seasonal mood disorder syndrome was not rare (10% of all mood disorders); diagnostic distribution was as follows: recurrent depression, 51%, and bipolar disorder, 49%, with 30% of the latter having mania (bipolar disorder type I) and 19% having hypomania (bipolar disorder type II). Most patients were women (71%); onset age averaged 29 years, with a mean of eight cycles in 12 years of illness; mean episode duration was 5.0 months. Mood disorder was found in a high proportion (68%) of the families. All but one patient followed one of two seasonal patterns in equal frequency: type A, fall-winter depression with or without spring-summer mania or hypomania; and type B, spring-summer depression with or without fall-winter mania or hypomania. Both types showed consistent times of onset and remission. These results emphasize that DSM-III-R seasonal mood disorder includes severe cases of recurrent depression and bipolar disorder and support a distinction between two seasonal subtypes.

Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania.

OBJECTIVE: The authors reviewed available evidence regarding the status of dysphoric or mixed mania as a distinct clinical state and formulated operational criteria for its diagnosis. METHOD: Studies of dysphoric mania or hypomania in patients with bipolar disorder were analyzed with regard to clinical characteristics, prevalence, demographic features, course of illness, outcome, family history, associated conditions, biological tests, and response to biological treatment. RESULTS: Although some studies suggest that dysphoric and nondysphoric mania are similar conditions, others suggest that, compared with nondysphoric mania, dysphoric mania may be more severe; more likely to occur in women; more likely to be associated with suicidality, a younger age at onset, a longer duration of illness, higher rates of personal and familial depression, concomitant alcohol or sedative-hypnotic abuse, neuropsychiatric abnormalities, and poorer outcome; more frequently associated with cortisol nonsuppression; and less likely to respond adequately to lithium but perhaps more likely to respond to ECT or anticonvulsants. CONCLUSIONS: Substantial evidence suggests that dysphoric mania may be a distinct affective state. Contrary evidence, however, suggests that dysphoric mania may be a form of typical mania, a stage-related or severe form of mania, or a transitional state between mania and depression. Because the evidence may be inconsistent because of varying definitions of dysphoric mania among studies, the authors propose preliminary operational diagnostic criteria for the future study of dysphoric mania.

Comorbidity in mania at first hospitalization.

Comorbidity was studied in 41 manic and mixed-state bipolar patients at first hospitalization. The lifetime prevalence of comorbidity was high; 21 subjects (51.2%) had at least one other psychiatric diagnosis (N = 16, 39.0%) or medical disorder (N = 9, 22.0%). Nine subjects had multiple comorbid diagnoses. Women were 2.7 times more likely to have a comorbid diagnosis. The presence of comorbidity was not associated with differences in outcome measures.

Possible affective-state dependence of the Tridimensional Personality Questionnaire in first-episode psychosis.

The authors administered the Tridimensional Personality Questionnaire (TPQ) to 61 patients with first-episode psychosis. Subjects were classified into affective states according to DSM-III-R diagnoses. TPQ scores were compared among these states and correlated with two affective symptom subscales: "mania" and "depression." Manic subjects demonstrated little variation from normative TPQ scores. Compared with findings in manic subjects, the dimensional score for Harm Avoidance was elevated in all affective groups, "worry and pessimism" was elevated in mixed-state subjects, "shyness with strangers" was elevated in depressed and nonaffective subjects, and "attachment" was lower in depressed and nonaffective subjects. The Harm Avoidance dimensional score and two subdimensional scores were positively correlated with the "depression" subscale. The Harm Avoidance dimensional and subdimensional scores showed possible affective-state dependence that may limit the utility of this instrument as a personality measure in first-episode psychosis.

The McLean First-Episode Psychosis Project: six-month recovery and recurrence outcome.

The McLean First-Episode Psychosis project began in 1989. The authors describe the study design, diagnostic distribution, and recovery and relapse data on the first 102 recruited subjects. Fifty-nine percent of the subjects had a diagnosis of bipolar disorder, 15 percent psychotic depression, 10 percent schizophrenic spectrum, 9 percent delusional disorder, and 8 percent other psychotic disorders. By 6 months, 80 percent recovered syndromically but only 55 percent recovered functionally, and only 50 percent recovered both functionally and syndromically. Non-white and male patients were more likely to have a recurrence. Men were less likely and bipolar patients were more likely to recover functionally. Patients with nonaffective psychosis had longer hospitalizations and lower rates of functional recovery 6 months after discharge.