Statistical approaches to trial durations in episodic affective illness.

In light of the high variability in illness characteristics and patterns among patients with bipolar illness, parallel group designs present severe methodologic difficulties. Crossover, off-on-off-on (B-A-B-A), and other individualized designs may be a useful substitute, but no consensus exists about how to estimate the individual trial durations required in these instances. Several methods for determining optimum trial lengths in crossover designs are presented, illustrated, and discussed. These include: chi-square (chi2) for the expected versus observed number of either episodes or days well; exceeding two standard deviations for average duration of episodes or euthymic intervals; or the Sequential Probability Ratio Test (SPRT), which detects when mean values differ from prior statistical expectations. Each method was applied to three demonstration cases using data from actual clinical trials of three patients with different patterns of recurrent affective illness. Each method detected changes in illness severity, although different tests appeared to be sensitive to differing cycle patterns in the patients illustrated. We suggest that these types of analyses and others can be used as indicator statistics to augment global impressions and clinical judgment, and to assist in determining individualized trial durations, both in formal clinical trials and in clinical treatment settings. Once individual responsivity is confirmed with an appropriate interplay of trial design and statistical analysis, the percentage response in a given population can then be compared to other agents or in other populations. Moreover, meta-analytic techniques based on addition of z scores from individuals' effect sizes can then be used to assess overall significance of a drug effect in a given population or subpopulation. The need for further development of appropriate and alternate study designs and analysis methods for bipolar illness is highlighted. Approaches to estimating required trial durations in individuals with different cycle frequencies in crossover and B-A-B-A designs constitute one element of that exploration.

Antidepressant-induced mania and cycle acceleration: a controversy revisited.

OBJECTIVE: The longitudinal course of 51 patients with treatment-refractory bipolar disorder was examined to assess possible effects of heterocyclic antidepressants on occurrence of manic episodes and cycle acceleration. METHOD: Using criteria established from life charts, investigators rated the patients' episodes of mania or cycle acceleration as likely or unlikely to have been induced by antidepressant therapy. Discriminant function analyses were performed to assess predictors of vulnerability to antidepressant-induced mania or cycle acceleration. Further, the likelihood of future antidepressant-induced episodes in persons who had had one such episode was assessed. RESULTS: Thirty-five percent of the patients had a manic episode rated as likely to have been antidepressant-induced. No variable was a predictor of vulnerability to antidepressant-induced mania. Cycle acceleration was likely to be associated with antidepressant treatment in 26% of the patients assessed. Younger age at first treatment was a predictor of vulnerability to antidepressant-induced cycle acceleration. Forty-six percent of patients with antidepressant-induced mania, but only 14% of those without, also showed antidepressant-induced cycle acceleration at some point in their illness. CONCLUSIONS: Mania is likely to be antidepressant-induced and not attributable to the expected course of illness in one-third of treatment-refractory bipolar patients, and rapid cycling is induced in one-fourth. Antidepressant-induced mania may be a marker for increased vulnerability to antidepressant-induced cycle acceleration. Antidepressant-induced cycle acceleration (but not antidepressant-induced mania) is associated with younger age at first treatment and may be more likely to occur in women and in bipolar II patients.

CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI.

Recently several steroid compounds have been discovered to act as neuromodulators in diverse central nervous system (CNS) functions. We wondered if neuroactive steroids might be involved in affective illness or in the mode of action of mood-regulating medications such as carbamazepine. Levels of the neuroactive steroids pregnenolone and progesterone, as well as the neuropeptide diazepam binding inhibitor (DBI) (known to promote steroidogenesis), were analyzed from cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) from 27 medication-free subjects with affective illness and 10 healthy volunteers. Mood-disordered subjects who were clinically depressed at the time of the LP had lower CSF pregnenolone (n = 9, 0.16 ng/ml) compared with euthymic volunteers (n = 10, 0.35 ng/ml; p < 0.01). In addition, pregnenolone was lower in all affectively ill subjects (n = 26, 0.21 ng/ml), regardless of mood state on the LP day, than healthy volunteers (p < 0.05). No differences were found for progesterone or DBI levels by mood state or diagnosis. Progesterone, pregnenolone, and DBI did not change significantly or consistently in affectively ill subjects after treatment with carbamazepine. CSF pregnenolone is decreased in subjects with affective illness, particularly during episodes of active depression. Further research into the role of neuroactive steroids in mood regulation is warranted.

Lithium-discontinuation-induced refractoriness: preliminary observations.

The authors used a systematic life-chart methodology to observe four patients with bipolar disorder in whom long periods (6-15 years) of effective lithium prophylaxis were followed by relapses on lithium discontinuation. Once the drug was reinstituted, it was no longer effective. The incidence, predictors, and mechanisms underlying this phenomenon all require further systematic study. The current preliminary observations suggest an additional reason for caution when lithium discontinuation in the well-maintained patient is considered.

The effects of carbamazepine on resting metabolic rate and thyroid function in depressed patients.

Resting metabolic rate and thyroid hormone levels were studied in 11 patients with affective disorders before and during treatment with carbamazepine (CBZ). CBZ has been previously reported to reduce thyroid hormones, but the metabolic consequence of this effect has not been explored. During CBZ treatment, thyroid hormones decreased significantly (T4, 7.53 versus 5.74 micrograms/dl, p less than 0.001), whereas the resting metabolic rate (RMR) did not (31.6 versus 30.7 kcal/m2/hr). Baseline RMRs were low and the expected positive relationship between RMR and weight was disrupted in females. The extent of previous exposure to tricyclic and monoamine oxidase inhibitors antidepressant treatment was significantly associated with lower baseline RMRs. We conclude that CBZ has no significant effect on RMR despite robust decreases in thyroid function.

Contraction of frog myocardium in non-uniform electromagnetic field.

Tension of the frog heart irradiated by nonuniform electromagnetic field was investigated. Tension changes up to 50% of initial values were observed. The presence of a.c. field gradient is viewed as a possible reason for such alterations.