Charles L. Bowden

Effects of lithium on platelet ionic intracellular calcium concentration in patients with bipolar (manic-depressive) disorder and healthy controls

Lithium is an effective drug in the treatment of both manic and depressive episodes of bipolar disorder. Lithium has been shown to block the metabolism of the intracellular second messenger inositol-1,4,5-trisphosphate which is involved in the rise in ionic intracellular calcium [( Ca++]i) which triggers neurotransmitter release and other cellular changes in secretory cells. We have measured the effect of lithium on [Ca++]i dynamics in platelets from bipolar patients stabilized with lithium treatment, and from healthy controls. Both resting [Ca++]i and the thrombin stimulated increase in [Ca++]i were higher in bipolar patients than in controls. Lithium added in vitro tended to increase the thrombin-stimulated rise in [Ca++]i. The use of the fluorescent Ca++ probe fura-2 in human platelets provides a useful method to investigate the mechanism of lithiums action in bipolar disorder and to study Ca++ related systems which may be abnormal in bipolar disorders.

Maintenance therapies for classic and other forms of bipolar disorder

The progressive, episodic and chronic nature of bipolar disorder dictates the need for lifelong pharmacological maintenance treatment in the majority of patients. Prophylaxis should be considered after a single episode of severe mania or after more than one episode of hypomania in bipolar II disorder, although some clinicians now consider an episode of either sufficient to warrant maintenance therapy. Lithium is efficacious as maintenance therapy, but is not as highly effective as early studies initially suggested (abrupt discontinuation of lithium probably increased placebo relapse figures). Rates of premature discontinuation of lithium are high. Divalproex sodium is used frequently in the USA and Canada for long-term treatment for bipolar disorder but an insufficient number of controlled trials have been published to assess adequately its role. Carbamazepine is also employed in maintenance treatment. Randomized studies indicate it is superior to placebo but somewhat less effective than lithium. Augmentation of any of these drugs with another mood stabilizer, an antipsychotic, or electroconvulsive therapy appears to be effective, although there are few controlled studies. Design issues that need consideration in order to achieve meaningful data are discussed. A severe manifestation of bipolar disorder is rapid cycling. It is often induced by antidepressants, although this association frequently goes unrecognized. Patients with a rapid cycling course of illness are difficult to treat effectively. Although rapid cycling is often associated with poor response to lithium, there have been no randomized, controlled treatment studies. Based on open studies and expert panel recommendations, the International Exchange on Bipolar Disorder (IEBD) recommended initial treatment with divalproex sodium, with subsequent addition of other mood stabilizers, antipsychotics or thyroid supplementation as necessary. Combination treatments are frequently required for optimal response in these patients.

EGTA-extractable calmodulin in platelet membrane is lower in alcoholics than in controls

The purpose of this study was to determine calmodulin distribution in platelets of alcoholics. Eight alcoholics were diagnosed by DSM-III (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition) criteria prior to admission to the Alcohol Unit, VA Hospital, San Antonio, TX. Whole blood was drawn after a five day washout period, and again after 30 days of disulfiram treatment. Platelets were prepared from the whole blood, suspended in Ringers-citrate-dextrose buffer (RCD), divided into 2 aliquots, then sonicated and centrifuged (100K X g). Supernatants were assayed for calmodulin content by RIA. The pellets were resuspended by sonication in 1 mM EGTA in RCD or 1% (w/v) Lubrol-PX in RCD, then centrifuged at 100K X g. Calmodulin was measured in the EGTA and Lubrol supernatants. EGTA-extractable calmodulin in pre-disulfiram, post-disulfiram, and control subjects was 5.07 +/- 2.2 (SD), 5.19 +/- 1.7 (SD), and 10.5 +/- 6.7 (SD) ng calmodulin/mg whole platelet protein. The EGTA-extractable calmodulin was significantly lower in alcoholics pre- or post-disulfiram than in controls (p less than 0.025). These preliminary results suggest an alteration in platelet membranes of alcoholics that affects the binding of calmodulin.

Non-specific neuroleptic isomer effect on calmodulin-stimulated calcium transport in erythrocyte membrane

Calmodulin-stimulated calcium transport by everted erythrocyte membrane vesicles was inhibited by equivalent doses of active and inactive isomers of the neuroleptic drugs butaclamol and chlorprothixene. However, the trans-isomer of flupenthixol, which lacks neuroleptic properties, inhibited calcium transport more than did the active cis-isomer. The drug concentrations required for inhibition greatly exceeded those serum levels necessary for neuroleptic activity. These results are consistent with a non-specific inhibition of calmodulin-activation of calcium transport by neuroleptic drugs and provide further evidence that this effect is unrelated to clinical antipsychotic properties of these drugs. Effects on basal calcium transport activity indicate binding of neuroleptics at a site other than cytosolic calmodulin.