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To date, few prospective studies of life events and bipolar disorder are available, and even fewer have separately examined the role of life events in depression and mania. The goal of this study was to prospectively examine the role of negative and goal-attainment life events as predictors of the course of bipolar disorder. One hundred twenty-five individuals with bipolar I disorder were interviewed monthly for an average of 27 months. Negative and goal-attainment life events were assessed with the Life Events and Difficulties Schedule. Changes in symptoms were evaluated using the Modified Hamilton Rating Scale for Depression and the Bech-Rafaelsen Mania Scale. The clearest results were obtained for goal-attainment life events, which predicted increases in manic symptoms over time. Negative life events predicted increases in depressive symptoms within regression models but were not predictive within multilevel modeling of changes in depressive symptoms. Given different patterns for goal attainment and negative life events, it appears important to consider specific forms of life events in models of bipolar disorder.

Rapid cycling bipolar disorder (RCBD) is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a type of manic-depressive illness in which the patient experiences four or more episodes of mania and/or major depression per year. It was first reported as a consequence of the reduced effectiveness of lithium carbonate in the treatment and prophylaxis of this form of bipolar disorder (BD) in contrast to those with less frequent cycling. Among the anticonvulsants, there have been reports with different degrees of controlled data concerning carbamazepine, valproate, lamotrigine, topiramate, gabapentin and primidone. There is a paucity of double-blind studies, but what is available supports the use of lamotrigine. There is open data supporting the use of carbamazepine, valproate and topiramate. Regarding other classes, nimodipine may have specific utility in ultradian- (ultra-ultra-) or ultra-RCBD and there is double-blind data regarding the specific utility of olanzapine in RCBD. Low thyroid function may be a factor in development of RCBD; therapies aimed at elevating thyroid levels, even beyond the usual range, have frequently produced benefits in open trials. More research is needed into the possible therapeutic benefits of verapamil, bupropion, choline, light therapy and electroconvulsive therapy (ECT).

Effect size (ES) is a statistical concept that can be used to improve the interpretation of results from psychopharmacological studies. ES may aid interpretation of results when sample size is unbalanced or small or when units or levels of baseline measures differ across items. Usually, an investigator can define a threshold value for a clinically meaningful ES based on published data and clinical judgment or by resorting to conventions, e.g., a medium ES = 0.5 S.D., which can usually be discerned by the trained clinician. In the present study, we apply ES analysis to results from a study comparing the effectiveness of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized, acutely manic patients. One hundred seventy-six patients were randomly assigned to DIVAL, LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind, parallel group design for 21 days. The primary efficacy measure was the Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia, composed of the Manic Syndrome Score (MSS) from items that are relatively specific to the manic state, and the Behavior and Ideation Score (BIS), which reflects severe but nonspecific psychopathology. Improvement of the MSS after 5 days of treatment was difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%, PLA = 8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at this early point in treatment. Similarly, the ES for change on the MSS at the end of treatment indicated a large, readily observable improvement with both DIVAL (ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also indicated that the BIS is a less robust indicator of change to either drug. The ES at the end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and 0.25 for PLA-treated patients.

Objective: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships., Method: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia., Results: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml., Conclusions: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Twelve patients meeting DSM-IIIR criteria for mania received verapamil over a 2-week period, with dosing up to 360 mg/day. Severity of mania was measured at baseline and weekly by use of the Young Mania Scale. Plasma calcium and magnesium determinations and an ECG were obtained at baseline and after 2 weeks of treatment. Mean improvement was from a baseline of 32.4 to 12.8, -60.5%. Decreased severity of mania correlated significantly with increased plasma calcium. This result may lend a method for monitoring successful treatment of mania with calcium channel inhibitors.

Cerebrospinal fluid (CSF) amino acid concentrations were measured in six Bipolar I, eight Bipolar II, eight Unipolar, and four other and control patients. All but four were also studied after administration of probenecid. Fourteen amino acids showed significant correlations of concentrations with age of subjects. Significant diagnostic group differences were found for five amino acids; only that of tyrosine persisted after taking subject's age into account. Following probenecid administration, there were statistically significant changes in CSF concentration of several amino acids, but these changes were small and likely indicative of diurnal changes.

Calmodulin-activated calcium ATPase is a transport enzyme which establishes the normal level of intracellular ionized calcium in most cells. We have determined values for three parameters of this enzyme: E-t, the concentration in the membrane; Vmax, the maximal velocity, and Ka, the binding affinity for calmodulin. We assayed these parameters in erythrocyte membranes from lithium carbonate-treated bipolar subjects and from normal controls. Bipolar subjects have significantly increased levels of E-t compared with normal controls.

Lithium carbonate treatment for 2-3 weeks produced a significant decrease in the maximum velocity (Vmax) of serotonin (5-HT) uptake, a measure of the number of 5-HT uptake sites in blood platelets from bipolar patients. The decrease was more pronounced in bipolar manic patients than bipolar depressed patients. There was no significant affect on the affinity for 5-HT (Km) of the uptake sites in the platelets of manic or depressed bipolar patients although Km did decrease (indicating increased affinity) in the majority of subjects from both groups of patients. However, lithium treatment of at least 1 year duration was associated with significant increases in Vmax without affecting Km. Lithium in vitro, at concentrations up to 1 mM, had no effect on the Km or Vmax of 5-HT uptake in blood platelets of normal controls. The possible mechanisms of the inhibitory and stimulatory effect of lithium carbonate treatment on platelet 5-HT uptake are discussed.

For 98 affective disorder patients receiving lithium prophylaxis for a mean of 45 months, number of interepisode symptoms correlated with relapse rate. Response to prophylaxis appeared highly determined by prelithium frequency of episodes and duration of lithium treatment.

Twelve patients who met Research Diagnostic Criteria for a history of bipolar affective disorder gave informed consent for open discontinuation of lithium therapy for 3 weeks. There was no significant change after lithium discontinuation in the number of depressive or manic symptoms, in mood score, in total Zung Depression score, or in any of the 20 items found in the Zung Depression scale. There were significant reductions in total severity of side effects, and improvement in the three side effects reflecting renal function: polydipsia, polyuria, and nocturia. These changes were reflected in the significant increase in urine specific gravity. Significant changes in side effects did not take place until at least 2 weeks after lithium was discontinued. Other significant relationships were found between increases in serum thyroid hormone levels and in urine specific gravity, and decreases in Vmax of platelet serotonin uptake and increases in degree of clonidine-induced hypotension.

The elimination half-life of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorders. The duration of lithium treatment at the time of sampling was found to have a direct effect on lengthening time-course. Those on their initial course of lithium had the lowest half-lives (in days): 1.12 (urine), 1.28 (plasma), and 1.22 (red blood cells); those with less than 1 year of lithium had intermediate values: 1.85, 1.65, and 1.75, and those with more than 1 year of continuous lithium administration had the highest mean half-lives: 2.40, 2.43, and 2.24. The significance of these results for urine (p less than 0.01) and plasma (p less than 0.05) indicates further evidence that lithium may stimulate the production of an endogenous regulator of lithium efflux. 8 of these patients had lumbar punctures before lithium administration: those with previous treatment with lithium had higher mean cyclic adenosine monophosphate levels than those taking it for the first time. These results are discussed in the context of the possible mechanisms of lithium action.

Efflux of lithium from human erythrocytes was studied in patients before, during, and after discontinuation of administration of lithium carbonate. Onset of lithium-induced repression of efflux took approximately 10 days and was significantly shorter in patients who had had lithium therapy previously. Reactivation took a longer period of time--approximately 2 week--and was found to be related to duration of lithium therapy. Theoretical pathways of lithium flow through membranes are discussed.

There were no differences in interepisode functioning or side effects between bipolar patients (N = 44) with plasma lithium levels above the median and those with levels below the median. Low levels were able to stabilize mood and individual symptoms for 40.5 months.

A prospective 1-year study was conducted in 69 patients with affective disorder. Despite remission, there was a significant continued presence at each visit of major symptoms of mania and depression and of mean mood shift. Furthermore, sub-clinical affective symptoms, as determined by General Behavior Inventory self-rating scores completed at 4 month intervals, continued at a level throughout the entire year significantly higher in patients than in 14 normal controls. Finally, as expected, presence of subclinical symptoms on the GBI correlated significantly with presence of major symptoms and mood shift. Correlation varied from 0.55 to 0.61; all significances were less than 0.001.

A new self-rating scale, the General Behavior Inventory (GBI), was lower in eight controls and 61 patients in remission than in 32 depressed patients. Scores of depressed patients decreased over treatment time. GBI score correlated significantly with the past occurrence of manic plus depressive symptoms per visit and past mean mood shift per visit.