Ronald R. Fieve

Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing.

Abstract: Pregabalin is a new anxiolytic that acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the α2-δ subunit of voltage-gated calcium channels. The current study evaluated the anxiolytic efficacy of BID versus TID dosing of pregabalin in patients with generalized anxiety disorder. Outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition generalized anxiety disorder and having baseline Hamilton Anxiety (HAM-A) total scores ≥20 were randomized to 6 weeks of double-blind treatment with pregabalin 200 mg/d (BID; N = 78), 400 mg/d (BID; N = 89), or 450 mg/d (TID; N = 88) or placebo (N = 86). Mean improvement in HAM-A total score at last observation carried forward end point was significantly greater on pregabalin 200 (P = 0.006), 400 (P = 0.001), and 450 mg/d (P = 0.005) compared with placebo. Pairwise comparisons of BID versus TID dosing found no difference in HAM-A change score at end point. All 3 pregabalin dosage groups showed significantly greater efficacy versus placebo at end point on the HAM-A psychic and somatic anxiety factor scores. Improvement on both factors was rapid: significance versus placebo was achieved as early as the first assessment at week 1, with ≥30% reduction in HAM-A severity and equal or greater improvement for every subsequent visit in ≥38% of patients in all 3 pregabalin dosage groups (P ≤ 0.001). Pregabalin was well tolerated, and despite the fixed-dose study design, discontinuations caused by adverse events ranged from 9% to 13%-comparable with that observed with placebo (8%). This study demonstrates that pregabalin is an effective treatment of generalized anxiety disorder, with BID dosing showing similar efficacy and comparable tolerability with TID dosing.

Bipolar Illness: A Prospective Study of Life Events

Abstract The purpose of the following is to present initial results from a prospective study of life events as precipitants of affective episodes. The role of life stresses in the etiology of affective episodes has been evaluated by several investigators. 1–3 In general, these reports consisted of interviews of depressed patients concerning life events which occurred at some time prior to the onset of their episode. The data obtained were retrospective in nature (asking patients to recall events in the recent past), a method which may be subject to error in terms of determining if the event actually occurred and when the event occurred in relation to the actual onset of affective symptoms. 4 Furthermore, prior studies have dealt with heterogeneous populations of affectively ill patients from a diagnostic viewpoint. We have studied life events prospectively in a group of well characterized bipolar manic-depressive patients. This preliminary report will focus on life events for the initial ten months in a subgroup of these patients, all of whom were bipolar and were being chronically treated with lithium carbonate.

The effect of lithium chloride administration on brain and heart norepinephrine turnover rates.

SummaryThe effect of Li+ on NE turnover rates in rat heart and brain was studied. Turnover rates were determined in brain and heart by blocking tyrosine hydroxylase with L-α-methyltyrosine and following the decline of NE with time or in heart by injecting3H-NE and following the decline of NE specific activity with time. Subacute treatment with LiCl in doses that maintained a serum lithium level within the clinically therapeutic range caused:1.A 95% increase in brain NE turnover rate without altering the steady-state level of the amine.2.A slight but not significant increase in heart NE turnover.3.The selective increase in brain NE turnover, compared to heart, may be attributed to the higher tissue levels of Li+ found in the brain under the conditions of study.

Sociotropy and autonomy: Relationship to antidepressant drug treatment response and endogenous-nonendogenous dichotomy.

This study evaluated the relationship of sociotropic and autonomous personality traits with response to pharmacotherapy for 217 depressed outpatients using the Sociotropy-Autonomy Scale. Sociotropy was related to nonendogenous depression, whereas autonomy was related to endogenous depression. Subjects who had high autonomous-low sociotropic traits showed greater response to antidepressants (and greater drug-placebo differences) than those who had high sociotropic-low autonomous traits (who showed no drug-placebo differences). Hierarchical multiple regression analysis showed that the sociotropy-autonomy, but not the endogenous-nonendogenous, distinction was a predictor of drug treatment response. The combination of endogeneity and autonomy predicted response to placebo. If replicated, these findings may enable better matching of patient traits to various treatment modalities for depression.

Disappearance of memory deficits in outpatient depressives responding to imipramine

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

Statistical predictions of suicide in depressives

The purpose of the present study was to determine how accurately suicide potential could be identified among patients with primary affective disorder by means of multivariate statistical procedures. Among patients with this disorder, suicide has been estimated to be about 30 times more prevalent than in the general population1 and to be the cause of death in about 15% of patients.2 However, many patients with depressive disorder never attempt suicide or become preoccupied with suicidal thoughts. The present study is concerned with identifying some of the factors that distinguish the suicidal from the nonsuicidal depressive. A number of studies to derive predictions of suicide potential by multivariate statistical means have appeared recently. Some that have applied vague predictor variables and met with little success have been reviewed elsewhere.3 Others have been concerned with a diagnostically heterogeneous group of patients with a history of suicide attempts in order to determine prognostic factors associated with repeated attempts.4,5 In contrast, the present study was concerned with a diagnostically homogeneous group that is heterogeneous with regard to suicidal behavior. These patients were classified as attemptors, contemplators, or nonsuicidals according to their responses in a structured interview, and the ability of predictor variables to identify membership in one of these groups was assessed by means of discriminant function analysis. The predictor variables were age, sex, marital status, diagnostic subtype, family history of suicidal behavior, and scaled ratings of work impairment and social isolation.

Social outcome compared in psychotic and nonpsychotic bipolar I patients.

Eighty-nine bipolar I patients were given a structured interview, the Schedule for Affective Disorders and Schizophrenia. Those who had experienced delusions or hallucinations at some time during the course of their illness were designated “psychotic,” and those who had not were designated “nonpsychotic.” The two groups were compared with regard to a number of outcome variables as well as age, age at first treatment, and duration of illness. The psychotic group had significantly poorer outcome in terms of social functioning. Although age, age at first treatment, and duration of illness distinguished between the two groups of patients, statistical analyses indicated that these variables did not account for differences in social outcome.

Repression of a lithium pump as a consequence of lithium ingestion by manic-depressive subjects.

The lithium pump in human erythrocyte membranes, which is responsible for extrusion of lithium against a concentration gradient, has been found to be reversibly repressed during periods of lithium carbonate administration. The pump activity of patients prior to lithium therapy is not different from controls. The onset of repression may require several days to several weeks and occurs at specific individual threshold levels of lithium carbonate dosage. Reactivation of the lithium pump occurs sometime after the dosage is discontinued. We postulate that repression of the lithium pump results from systemically available factors which alter membrane structure, and suggest that if such changes also occur in the central nervous system, they may provide insight into one means by which lithium produces its psychotropic affects.

Mechanisms of renal lithium handling and their relationship to mineralocoticoids: A dissociation between sodium and lithium ions

Abstract Lithium-induced alterations in electrolyte excretion were studied in 16 patients with manic-depressive disease and in one normal subject under conditions of controlled sodium, potassium and fluid intake. An increase in urinary sodium and potassium excretion and in urine volume were noted on the first day of lithium administration. By lithium day 3, transient sodium retention occured. These changes in electrolyte excretion were not correlated with measurable changes in endogenous creatinine clearance. Sodium loading diminished and sodium depletion increased lithium retention. While sodium depletion always raised serum lithium levels, in one patient signs of lithium toxicity appeared despite relatively low serum lithium concentrations. These observations suggest that serum lithium may not be an accurate indicator of lithium overdose, especially during states of acute sodium depletion. Chlorothiazide and the aldosterone antagonist spironolactone produced a striking sodium diuresis, but lithium excretion did not increase consistently and at times decreased. Differences in renal sodium and lithium handling were also observed in response to desoxycorticosterone acetate (DOCA) administration. In rats, DOCA failed to cause lithium retention despite prompt retention of sodium. During the DOCA ‘escape’ period, lithium excretion increased and serum lithium concentration fell. Thus, renal lithium handling, unlike sodium handling, appears independent of mineralocorticoids. These characteristics of lithium excretion during DOCA administration in rats and aldosterone blockade in man suggest that the proximal tubule is the major site of lithium reabsorption in these species. These in vivo studies in man and animals indicate a decreased capacity of active transport systems in the kidney to handle the lithium ion as effectively as the sodium ion. These differences in sodium and lithium handling by the kidney may be related, in part, to lithiums mechanism of action, particularly if active transport systems in the central nervous system are qualitatively similar to those of the kidney with respect to lithium handling.

Psychosis as a predictor of response to lithium maintenance treatment in bipolar affective disorder.

Sixty-six bipolar I lithium clinic patients were studied for a history of psychotic symptoms at some time during the course of their illness. Agreement between different sources of information was calculated, and the patient population was divided into psychotic and non-psychotic subgroups. Probability of remaining well on lithium for the different subgroups was analyzed by the life table method. Psychosis during mania appeared to be associated with especially good early lithium prophylaxis.