The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal methodology.

The NIMH-Stanley Foundation Bipolar Treatment Outcome Network, a multisite clinical trials network, has been established to address many of the neglected areas of research in bipolar illness. The Network was designed so that it would be able to conduct randomized clinical trials at several different levels of methodologic rigor (blinded and open-label) both in academic and community practice settings in order to better assess long-term efficacy of existing treatments and develop new ones. In this fashion, large numbers of representative patients with bipolar disorder have been enrolled with an additional focus of elucidating possible clinical and biological predictors of treatment response. The unique focus of the Network is its systematic longitudinal approach to illness so that patients can be assessed comprehensively over the long-term in sequential randomized clinical trials at critical clinical decision points where data on relative efficacy are inadequate. Bipolar I and bipolar II patients with a range of illness variants and comorbidities are included. Daily prospective ratings of severity of mania and depression and associated degree of functional impairment are completed on the NIMH-Life Chart Method and a modified Clinical Global Impressions Scale for Bipolar Illness (CGI-BP) is utilized. More detailed cross-sectional ratings for depression (Inventory of Depressive Symptomatology), mania (Young Mania Rating Scale), and psychosis (Positive and Negative Syndrome Scale) are additionally used at academic centers. This article describes the rationale for the Network, its guiding principles, methods, and study design to systematically assess the highly variable course of bipolar illness and its response to current and future treatments.

Rapid cycling bipolar affective disorder: lack of relation to hypothyroidism.

Thyroid indices were measured after an extended period of medication-free evaluation averaging 6 weeks in 67 consecutively admitted patients with bipolar illness. Thyroid hormone levels -- thyroxine (T4), free T4 and triiodothyronine (T3) -- were not significantly different in the 31 rapid cyclers (> or = 4 affective episodes/year) than in 36 non-rapid cyclers. Analysis of covariance indicated a non-significant trend relation between higher T4 and a greater number of affective episodes in the year prior to admission and male gender when age was covaried. Several previous reports, primarily in medicated subjects, have suggested a link between rapid cycling patients and decreased peripheral thyroid indices (low hormone levels and elevated TSH), but now the majority of studies do not support such a relation. Among those in the literature, this study includes patients studied for the longest time off medications and further suggests that the commonly-cited relation between subclinical hypothyroidism and rapid cycling bipolar illness be reevaluated.

Ultra-rapid and ultradian cycling in bipolar affective illness.

BACKGROUND: Rapid-cycling bipolar disorder is defined as four or more affective episodes yearly. The conventionally recognised limit in episode duration is usually considered 24 hours (i.e. a cycle duration of 48 hours). We report a small series of intensively observed bipolar patients who showed much faster patterns of mood oscillation. METHODS: Detailed, systematic, longitudinal assessment of five bipolar patients during extended in-patient psychiatric evaluation were conducted, including retrospective life charting and prospective evaluation of daily mood by self and blinded observer ratings, and motor activity recording. RESULTS: Our data demonstrate a spectrum of cycling frequencies in rapid-cyclers, including distinct, clinically robust mood shifts that occur at frequencies faster than once per 24 hours. Affective oscillations spanned a range of cycling frequencies from four episodes per year (rapid cycling) to those occurring within the course of weeks to several days (ultra-rapid cycling), to distinct, abrupt mood shifts of less than 24 hours duration (ultra-ultra rapid or ultradian cycling). The time of onset and duration of these ultradian affective fluctuations are highly variable and they are observed in bipolar patients without evidence of personality disorder. CONCLUSIONS: The potential clinical and theoretical implications of these first systematic observations of ultra-rapid and ultradian cycling in the context of the evolution of otherwise classical bipolar affective illness are discussed.

Rash complicating carbamazepine treatment.

Carbamazepine--widely used in the treatment of trigeminal neuralgia, seizure disorders, and more recently, manic-depressive illness--is generally safe and well tolerated. Although serious adverse reactions, such as hematologic toxicity, may occur rarely, we have found that carbamazepine-induced rash is common, occurring in 13 (12%) of 113 patients. We describe our experience with carbamazepine-induced rash, including clinical characteristics, demographic features, and associated laboratory findings. Integrating our findings with the literature, we also discuss incidence, possible mechanisms, and implications for treatment because these benign rashes can occasionally progress to more fulminant and life-threatening eruptions.

Addition of lithium carbonate to carbamazepine: hematological and thyroid effects.

In view of the increasing use of lithium-carbamazepine combination therapy for refractory psychiatric disorders, the authors assessed the clinical laboratory effects of adding lithium to carbamazepine in 23 patients with affective disorders. Lithium produced a robust reversal of carbamazepine-induced leukopenia, increasing WBCs, predominantly neutrophils, to levels significantly above placebo baseline values. The combination produced additive antithyroidal effects, resulting in greater decreases in T4 and free T4 than with carbamazepine alone; the addition of lithium was associated with the emergence of a modestly higher TSH level. The authors discuss clinical and theoretical implications of these findings.

Treatment of rapid cycling bipolar illness.

Rapid cycling patients (greater than or equal to 4 episodes/year) often show inadequate response to lithium carbonate and are vulnerable to antidepressant-induced switches or cycle acceleration. Treatment with the anticonvulsant carbamazepine is now an accepted adjunct or alternative, and a series of uncontrolled studies also suggest the utility of valproate in this patient population. Clonazepam, suppressive doses of thyroid, calcium channel blockers, and other innovative treatments appear promising and deserve careful clinical investigation.

The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression.

The addition of lithium carbonate to various antidepressant agents, including heterocyclics and monoamine oxidase inhibitors, has been reported to rapidly effect an antidepressant response in otherwise treatment-unresponsive depressed patients. Fifteen depressed patients diagnosed by DSM-III criteria who had not responded to double-blind treatment with carbamazepine were treated with the blind addition of lithium to carbamazepine. Eight patients (53%) responded with a moderate to marked improvement. The time to onset of substantial clinical improvement was rapid; ie, the mean (+/- SD) was 4.1 +/- 2.4 days for lithium potentiation compared with 9.7 +/- 4.1 days in a separate group of depressed patients responding to lithium alone. Side effects during carbamazepine-lithium combination therapy were minimal. The mechanisms by which lithium appears to rapidly potentiate the effects of carbamazepine in treatment-resistant depression are discussed.

Effect of cyclical unipolar depression on upper gastrointestinal motility and sleep.

Cyclic 48-h unipolar depression is a rare form of recurrent affective disorder. We studied a single patient to determine (a) if there is an association between psychiatric status and migrating motor complex activity; and (b) if phase III of the migrating motor complex is in phase with rapid eye movement sleep in depression. There was marked reduction in phase III of the migrating motor complex during the depressed (n = 7) compared with the euthymic phase (n = 13), and a lack of coherence between phase III migrating motor complex activity and sleep stages in both depressed and nondepressed phases. The depressed state may be associated with altered upper gastrointestinal motor function.

Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania.

Although lithium and carbamazepine used alone are effective in treating acute mania, some patients do not respond adequately to either of these medications used alone. We assessed, under double-blind conditions, a potential synergism between carbamazepine and lithium in the acute treatment of mania. Six of 7 manic patients who had previously been largely refractory to lithium alone, and who still showed substantial mania after several weeks of double-blind treatment with carbamazepine, improved following the blind addition of lithium. The clinical and theoretical implications of the response to this combination treatment are discussed.

Normal serum thyroxine values in patients with acute psychiatric illness.

The medical records of 278 consecutive patients with acute psychiatric illness admitted to a closed psychiatric unit after admission from the emergency room were reviewed. Serum thyroxine levels had been determined within 72 hours of admission in 106 patients (38 percent); in 74 of these patients (70 percent), the determination had been made within 24 hours. Ten patients (9 percent) were hypothyroxinemic, but further thyroid testing revealed that they were functionally euthyroid. Only one patient had hyperthyroxinemia, which was considered secondary to her postpartum state. The prevalence of hypothyroxinemia in the population studied is consistent with that in previous reports. However, the striking absence of hyperthyroxinemia in these patients is contrary to findings in several recent reports. Further prospective studies should clarify this issue.

Acute toxicity after excessive ingestion of colchicine.

A 15-year-old girl was admitted to a hospital in Rochester, Minnesota, 40 hours after the ingestion of 24 mg of colchicine. She suffered severe cardiovascular, pulmonary, hematologic, gastrointestinal, renal, metabolic, and neuromuscular complications but ultimately survived. Colchicine is an uncommon but potentially serious source of acute toxicity. An overdose warrants prompt attention in a setting where intensive medical support is available.

Are patients with chronic pain depressed?

Of 100 consecutive patients treated in a program for management of chronic pain, 25 were definitely depressed, 39 were probably depressed, and 36 were not depressed. Comparisons between the definitely depressed and nondepressed groups showed them to have strikingly similar characteristics as well as treatment outcome. Nearly 90% of the definitely depressed patients showed resolution of their depression without use of antidepressant medication.

Blood flow to the rabbit pancreas with special reference to the islets of Langerhans.

Nonradioactive microspheres of various sized (mean batch diameters ranging from 6 microns ato 26 microns) were administered to unfasted rabbits under sodium pentobarbital anesthesia by a brief injection into the left ventricle. Flow rate per bead was determined by the reference organ method. After prompt death of the animal, the spheres were located and counted miroscopically (islet vs. nonislet) in fixed, stained, and cleared portions of the pancreas. According to an analysis of the distribution of spheres as a function of bead diameter, 11-23% of the total pancreatic blood flow went directly to the islets and 77-89% to the "acini" (nonislet tissues). After retrograde postmortem injection of spheres 6 microns, 9 microns and 11 microns in diameter, practically none reached the islets, whereas after orthograde postmortem injection, they did so in the same proportions as in vivo. These results, supplemented by certain control experiments, support the view that all, or nearly all, efferent islet blood flow goes to the acinar capillaries before leaving the organ. We conclude that the arterial supplies to the rabbit exocrine and endocrine pancreas are in parallel, with most of the flow going to the exocrine portion. However, the flow to the islets is large enough to permit significant local actions of the islet hormones on the exocrine pancreas, in confirmation of the existence of an insuloacinar portal system.

Simple method for visualization of the islets in fixed but otherwise intact pancreas.

A simple, inexpensive, reproducible method is described for prominently displaying the islets of Langerhans. The method consists of sequential arterial perfusion of the organ of the sacrificed animal with saline, formalin, hematoxylin, and water, followed by clearing in methyl salicylate. The procedure should be useful whenever islet tissue needs to be quantitatively distinquished from non islet tissue and fixation is allowable.