Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15-year follow-up.

OBJECTIVE: Despite increasing interest in cognitive dysfunction in bipolar disorder, little is known about its impact on functional outcome relative to affective symptoms. METHOD: A total of 33 bipolar I subjects were evaluated at index hospitalization and prospectively followed up 15 years later. Affective symptoms, cognition, global functioning, work, and social adjustment were assessed at follow-up and analyzed by linear regression. RESULTS: Global functional impairment was significantly associated with poor performance on a cognitive measure of processing speed (WAIS Digit Symbol). Digit symbol performance also was the sole significant predictor of social functioning. Neither symptom severity nor course of illness features significantly contributed to global and social functioning. In contrast, verbal learning deficits, recent depression, and lifetime hospitalizations all were independently associated with work disability. CONCLUSION: Processing speed is robustly associated with social and global functioning in bipolar disorder. Poor work functioning is significantly related to subsyndromal depression, course of illness, and verbal learning deficits. Cognitive and mood symptoms warrant consideration as independent determinants of functioning in patients with bipolar disorder many years after an index manic episode.

Risk for bipolar illness in patients initially hospitalized for unipolar depression.

OBJECTIVE: To assess the risk for subsequent development of mania or hypomania, the authors conducted a 15-year prospective follow-up study of a large, young cohort of patients originally hospitalized for unipolar major depression. METHOD: Patients who were hospitalized for unipolar major depression (N=74; mean age=23.0 years, SD=3.8) were assessed prospectively as inpatients and then followed up five times over 15 years, at approximately 2, 5, 8, 11, and 15 years after discharge. Manic or hypomanic episodes, medications, and rehospitalizations were determined by standardized assessments at each follow-up. Polarity conversions were evaluated by survival analyses. RESULTS: By the 15-year follow-up, 27% of the study group had developed one or more distinct periods of hypomania, while another 19% had at least one episode of full bipolar I mania. Depressed patients with psychosis at the index depressive episode were significantly more likely than nonpsychotic patients to demonstrate subsequent mania or hypomania at follow-up. Those with family histories of bipolar illness showed a nonsignificantly higher rate of switching to mania or hypomania. Spontaneous and antidepressant-associated manias did not differ in frequency. Fewer than one-half of the patients who showed an eventual bipolar course had received prescriptions for mood stabilizers in any follow-up year. CONCLUSIONS: Young depressed inpatients with psychotic features may be at especially high risk for eventually developing mania. The probability for developing a bipolar spectrum disorder increases in linear fashion for patients at risk for polarity conversion during the first 10-15 years after an index depressive episode.

Cognitive side effects of anticonvulsants.

The increasing use of anticonvulsant drugs in psychiatry has prompted greater awareness of their effects on a range of psychiatric domains, including cognition. Older versus newer antiepileptic drugs have been reported to either worsen or enhance cognitive performance in clinical populations, and the extent to which cognitive disturbances may reflect iatrogenic factors versus psychopathology is subject to debate. We review current information about the role of anticonvulsants in cognition, with particular emphasis on newer compounds (such as lamotrigine, gabapentin, and topiramate), the cognitive dimensions of affective illness, and the clinical approach to evaluating cognition in psychiatric patients taking anticonvulsant drugs over time.

Citalopram as adjunctive therapy in bipolar depression.

BACKGROUND: The treatment of bipolar depression remains a major clinical challenge. The effectiveness and safety of adjunctive citalopram were evaluated in DSM-IV-diagnosed bipolar depressed patients in a 5-site study. METHOD: The treatment strategy consisted of an open-label add-on design in which patients received 8 weeks of acute treatment with citalopram adjunctive to their ongoing treatment with mood stabilizers. Ongoing treatment with 1 antipsychotic, 1 anxiolytic, and 1 hypnotic agent was permitted. Responders to the 8-week trial then received 16 weeks of additional treatment with citalopram. RESULTS: Forty-five subjects entered the trial; 12 dropped out before the end of the acute treatment phase. Of the 33 patients who completed the acute treatment phase, 64% (N = 21) were responders and 36% (N = 12) were nonresponders. In the continuation phase of the study, 14 patients achieved sustained remission, 3 patients did not achieve remission before completing 16 weeks of continuation treatment, 2 patients experienced a relapse, and 2 patients dropped out of the study and did not have a chance to remit. In spite of the extensive concomitant medication usage allowed in this study, citalopram treatment was well tolerated and the level of reported adverse events (including headache, nausea, diarrhea, and sexual dysfunction) relatively low. CONCLUSION: The high response rate, the high rate of sustained remission, and the low rate of adverse events strongly support the use of citalopram as a treatment for bipolar I or II depression. These findings should stimulate a controlled double-blind trial to demonstrate even more clearly the usefulness of this drug in the therapeutic regimen for bipolar disorder.

Suicidality and substance abuse in affective disorders.

The relationship between suicidality and substance abuse has long been recognized, although studies have only fairly recently begun to identify factors that may help clarify how alcohol or other drug abuse increases the susceptibility to suicidal behavior in vulnerable populations. In particular, alcohol and other psychoactive substance misuse has been linked with mood destabilization and the induction of manic or depressive episodes in affectively ill individuals, while also demarcating groups with heightened tendencies toward impulsivity, aggression, and sensitivity to interpersonal loss. Serotonergic mechanisms have been implicated in each of these clinical settings, along with possible dysregulation of other neurotransmitter systems. Psychosocial aspects of alcohol or drug abuse relevant to suicide may involve a heightened sensitivity to interpersonal loss, poor coping skills in response to adverse life events, and affective dysregulation induced by circadian and psychosocial stresses. Consequently, self-destructive behaviors with relatively little premeditation may arise during periods of increased stress, intoxication, depression, or other psychopathology. Early detection of substance abuse followed by appropriate pharmacologic and/or psychotherapeutic interventions may greatly help to minimize the formation of complex comorbid psychiatric conditions and reduce the potential for suicidal acts among high-risk populations.

Bipolar disorder with comorbid substance abuse: diagnosis, prognosis, and treatment.

Alcohol and drug abuse occur frequently in individuals with bipolar disorder, but clinicians may often feel ill-prepared to identify such multi-diagnosis syndromes, to contextualize drug abuse alongside affective symptoms, and to formulate appropriate treatment strategies. Plausible explanations for high comorbidity rates between bipolar illness and substance use disorders are complex and likely embrace numerous factors that extend beyond simple, older theories about drug use as sheer "self-medication." Evidence from epidemiologic, family-genetic, pharmacologic, psychosocial, and clinical psychopathology studies suggest that a majority of bipolar patients are at risk for developing lifetime drug or alcohol-related problems, which may in turn contribute to more varied and complex clinical presentations, accelerated relapses, worsening of depressive features, poorer lithium response, functional disability, and elevated suicide risk. In this article, the author reviews essential concepts about the phenomenology and treatment outcome of bipolar illness with substance use comorbidities and offers a systematic approach to the diagnosis and management of patients with such dual diagnoses.

Thought disorder in schizophrenia and mania: impaired context.

This research studied hypotheses that positive thought disorder in schizophrenia is influenced by patients' not taking in immediate target contextual material, thereby losing vital cues that guide thought processes. We assessed 164 acute inpatients (including 55 schizophrenia and 31 bipolar disorder patients), using standardized measures of thought disorder. We also used new measures that assessed (1) total ignoring of context, and (2) straying from the context. Results were as follows: (1) only 9 percent of the schizophrenia patients showed strong evidence of completely ignoring the external context; (2) straying from the external context while simultaneously maintaining part of the context was significantly more common than complete absence of context (p < 0.01); (3) patients with thought disorder strayed from the context significantly more than patients without thought disorder (p < 0.001); and (4) straying from the context was involved in the thought disorder of some, but not all, schizophrenia and mania patients. The data suggest that thought disorder in schizophrenia is not typically due to a failure to "hear" or to take in the relevant contextual material necessary for an appropriate response. Loss of context is involved in some, but not all, thought disorder in schizophrenia and mania.

Qualitative differences in manic symptoms during mixed versus pure mania.

Previous studies have compared demographic and clinical-outcome features of bipolar patients with mixed or pure mania. However, little is known about the potential differences in the nature and extent of manic symptoms in mania either with or without an accompanying depression. This study examined DSM-III-R manic symptoms in a cohort of 183 bipolar I inpatients hospitalized for mixed mania (diagnosed by broad or narrow criteria) or pure manic episodes. Inpatient charts were reviewed to determine the presence of individual affective symptoms. The results indicate that clinicians were more likely to diagnose a pure mania from the beginning to end of an episode than to diagnose a mixed mania from its beginning to end. Mixed-manic patients had significantly fewer manic symptoms than pure manic patients. Grandiosity, euphoria, pressured speech, and a decreased need for sleep were more prevalent during pure versus mixed mania. Grandiosity and a diminished need for sleep were especially notable during pure mania compared with mixed mania as defined by narrow criteria for mixed states. The observed differences in manic symptom profiles between mixed and pure mania may aid in the clinical assessment of dysphoric states among bipolar patients. The data also lend support to the use of broad diagnostic criteria for defining mixed mania as an entity phenomenologically distinct from pure mania.

New drugs in psychiatry.

Recent years have witnessed the rapid expansion of new psychotropic agents and psychotropic applications of primarily nonpsychiatric medications in nearly all domains of psychopathology. Increasingly, patients in emergency departments may be taking newer-generation antidepressants, antipsychotics, and mood-stabilizing drugs, and individuals with treatment-resistant psychiatric disorders are often prescribed complex, polypharmaceutical regimens. Current information on the use of psychiatric medications that have entered widespread use in the past 5 to 10 years is reviewed, with focus on indications and dosing, comparisons with older medications, management of patients with overdoses and toxicity states, and the medical and psychiatric effects of newer drugs on patients who may present to emergency departments.

Treatment guidelines: current and future management of bipolar disorder.

The emergence of new treatments for bipolar disorder has coincided with a proliferation of published treatment algorithm recommendations and practice guidelines. Several guidelines derive from critical appraisals of current treatment literature and, as such, may serve as a critical reference resource to complement individual clinical judgment. This review describes points of overlap and discordance across currently available treatment guidelines for bipolar disorder and presents common clinical situations in which the consultation of treatment guidelines may provide clinicians with useful information and a rationale for making sequential treatment decisions.

A history of substance abuse complicates remission from acute mania in bipolar disorder.

BACKGROUND: Substance abuse frequently complicates the course of bipolar illness, promotes mixed states, and contributes to poor outcome in mania. Preliminary open trials suggest that anticonvulsant mood stabilizers may enhance remission rates and outcome for bipolar patients with substance abuse. This study compared remission patterns for mixed or pure manic episodes among bipolar inpatients with or without substance abuse histories. METHOD: Hospital records were retrospectively reviewed for 204 DSM-III-R bipolar I inpatients. Clinical features were compared for those with or without substance abuse/dependence histories predating the index manic episode. Time until remission was analyzed by Kaplan-Meier survival analysis. Naturalistic treatment outcome with lithium or anticonvulsant mood stabilizers was compared for those with or without past substance abuse. RESULTS: Past substance abuse was evident in 34% of the bipolar sample and comprised most often alcoholism (82%), followed by cocaine (30%), marijuana (29%), sedative-hypnotic or amphetamine (21%), and opiate (13%) abuse. Substance abuse was more common among men (p < .05) and those with mixed rather than pure mania (p < .05). Remission during hospitalization was less likely among patients with prior substance abuse (p < .05), especially alcohol or marijuana abuse, and among mixed manic patients with past substance abuse (p < .05). Bipolar patients with substance abuse histories who received divalproex or carbamazepine remitted during hospitalization more often than did those who received lithium as the sole mood stabilizer (p < .05). CONCLUSION: These findings support previous reports suggesting that bipolar patients with past substance abuse have poorer naturalistic treatment outcomes, but may show a better response to anticonvulsant mood stabilizers than lithium.

Correlates of suicidal ideation in dysphoric mania.

BACKGROUND: Previous investigations have reported that suicidal ideation and behavior are more prevalent during mixed than pure mania. Uncertainties exist about whether suicidality in mania arises from multiple concurrent depressive symptoms, or rather, as a categorical phenomenon, reflecting dysphoria without necessarily a full major depression. To elucidate the relationship between suicidal ideation and dysphoric mania, we analyzed clinical and demographic features associated with suicidal versus nonsuicidal dysphoric manic inpatients. METHODS: Records were reviewed for 100 DSM-III-R bipolar I manic inpatients at the Payne Whitney Clinic of New York Hospital from 1991-1995. All had > or = 2 concomitant depressive symptoms (other than suicidality). Affective and psychotic symptoms, past suicide attempts, prior illness, and related clinical/demographic variables were assessed by a standardized protocol. RESULTS: Suicidal ideation was significantly more common among dysphoric manics who were caucasian, took antidepressant medications in the week prior to admission, had histories of alcohol abuse/dependence, and made past suicide attempts. Suicidal ideation was evident for nearly half of dysphoric manic patients with < or = 3 depressive symptoms who did not meet DSM criteria for a mixed state. No individual manic or depressive symptoms other than dysphoric mood were more common among suicidal than nonsuicidal patients. LIMITATIONS: Findings from this retrospective study require confirmation using a prospective assessment. Treatments were naturalistic and may have differentially influenced hospital course and illness characteristics. Factors related to suicide attempts (rare in this cohort) or completions (not a focus of this study) may differ from those related only to suicidal ideation. CONCLUSIONS: Caucasian dysphoric manic patients with past suicide attempts and substance abuse may have a significantly elevated risk for suicidality, even when full major depression does not accompany mania. Suicidality is a clinically important consideration in a majority of dysphoric manic patients.

Association of recurrent suicidal ideation with nonremission from acute mixed mania.

OBJECTIVE: The authors' goal was to examine suicidality in relation to acute symptom remission in inpatients with mixed and pure bipolar disorder. METHOD: Using chart review of 184 adult inpatients with bipolar I disorder, the authors assessed patients' past and current suicidality, other psychopathology, treatment, and remission. RESULTS: Past, current, and recurrent suicidality were significantly more common among patients with mixed mania than among those with pure mania. The probability of remission declined by 49% for every suicide attempt made before the index manic episode. Mixed mania, multiple previous hospitalizations, and previous suicide attempts were significantly associated with current suicidality. CONCLUSIONS: Suicidality is linked with mixed manic states and may be a clinical marker for recurrent dysphoric mania. Multiple suicide attempts are associated with nonremission from mixed manic episodes.

Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients.

BACKGROUND: Recent investigations have suggested that the antimanic agents divalproex sodium and carbamazepine may each hasten hospital discharge and be especially beneficial in treating mixed-state mania. This study retrospectively compared the time to remission for pure versus mixed manic bipolar inpatients who were taking lithium, divalproex, or carbamazepine, or their combination, under naturalistic conditions. METHOD: Records were reviewed for 120 bipolar inpatients from 1991 to 1995. Research DSM-III-R diagnoses of pure or mixed mania were assigned along standardized guidelines. Data were obtained on daily symptoms, medication doses, and blood levels. Weekly improvement was evaluated by Kaplan-Meier survival analysis of Clinical Global Impressions scale scores. Variables associated with "remission" versus "nonremission" were examined by logistic regression. RESULTS: Mixed mania (N = 70) was more common than pure mania (N = 50). No significant differences were observed in the time to remission for mixed or pure manic bipolar patients who took lithium compared with those who took divalproex or carbamazepine. In patients who remained symptomatic with lithium as a single-agent mood stabilizer despite therapeutic serum lithium levels, the addition of a second mood stabilizer led to rapid symptom improvement. Among all medication subgroups, the speed with which patients achieved therapeutic blood levels of any of these agents significantly affected the time to remission. CONCLUSION: Mixed manic bipolar patients taking lithium, divalproex, or carbamazepine under naturalistic conditions remit at comparable rates. Those failing to respond to single-agent mood stabilizers often receive combinations of mood stabilizers. However, delays in optimizing a medication regimen may attenuate short-term outcome, regardless of the mood stabilizer selected. Rapid achievement of therapeutic blood levels of any antimanic agent appears to be strongly related to swift symptom remission.

Course and outcome for schizophrenia versus other psychotic patients: a longitudinal study.

We studied 276 patients longitudinally, beginning at the acute phase and continuing at three successive followups over 7.5 years, comparing 74 schizophrenia patients with 74 other psychotic patients and 128 nonpsychotic patients on early course and outcome. Schizophrenia patients showed significantly poorer functioning than patients with other psychotic disorders at each of the three followups (p < 0.05). More schizophrenia patients than other psychotic patients showed consistent psychopathology and a course in which there was not complete remission at any of the three followups (p < 0.05). Most schizophrenia patients did not show severe decrements in social activity level. Poor outcome schizophrenia patients showed significantly slower recovery at each followup than did other psychotic patients with initial poor outcomes (p < 0.01). The results indicate that, during the early course, schizophrenia patients still show relatively poor outcomes, although a small number of schizophrenia patients enter into complete remission. Over time, many schizophrenia patients fluctuate between severe disability and moderate disability rather than always showing severe disability. Schizophrenia patients tend to recover more slowly then other psychotic patients. Differences between schizophrenia patients and other psychotic patients in clinical course over time may be larger than differences at any single followup.