Alan G. Mallinger - US grants

The studies proposed in this application will investigate cell membrane phenomena that may be related to the occurence of affective disorders, or to the treatment of such disorders with lithium (Li+). These studies will utilize the RBC membrane in a selective way as a model for certain aspects of membrane functioning. The first component of the investigation will be performed with carefully diagnosed (by RDC criteria), drug-free subjects from the following clinical categories: unipolar depressed; unipolar recovered; bipolar depressed; bipolar hypomanic; and control (new affectively ill). Current symptomatology will be assessed by means of observer- and self- administered clinical rating scales. The specific aims for this part of the project are to investigate the following biological areas in relation to clinical affective status: 1) modulatroy and intrinsic aspects of RBC membrane sodium (Na+) transport via the Na+-K+ pump; 2) carrier-mediated RBC membrane choline (Ch+) transport; and 3) RBC membrane composition of Ch+-, amino-, and inositol-phospholipids. Possible interrelationships among these various bilogical areas, as well as their relationships to clinical affective status, will be assessed. By collecting a variety of clinical and biological data from subjects representing several distinct diagnostic categories and clinical affective states, the project will attempt to develop a clearer understanding of membrane phenomena in relation to affective illness. In the second component of the investigation, hypomanic bipolar patients who have participated in the first component will be studied during Li+ treatment, in order to measure both Li+- induced membrane changes and therapeutic outcome. Specifically, the project will investigate treatment-related effects on RBC Na+ influx, plasma modulation of the Na+-K+ pump, membrane Ch+ transport, kinetic parameters of Na+-Li+ countertransport, and RBC membrane composition of Ch+-, amino- and inositol-phospholipids. Clinical and biological measurements will be performed prior to treatment, and will be repeated after 1, 2, and 4 weeks of Li+ therapy. In this way, the project will attempt to determine whether changes in one or more of these potentially interrelated membrane parameters are associated with corresponding changes in clinical affective state during Li+ treatment. The proposed research project might eventually lead to a better understanding of biological mechanisms in affective illness, or to new biological strategies for predicting treatment responsiveness.

A significant proportion of manic patients either do not respond adequately to conventional treatment (lithium with or without neuroleptics), or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Anticonvulsants are a frequently utilized second-choice treatment, but are ineffective in one third or more of patients. Thus, a need exists for additional effective treatments. Reports in the literature suggest that calcium channel blocking agents may also have antimanic actions. This is consistent with the notion that lithium, the prototypical antimanic drug, exerts its therapeutic action by attenuation of a receptor-mediated rise of intracellular calcium. However, the efficacy of calcium channel blockers as an alternative therapy in treatment-resistant mania has never been subjected to definitive study with adequate numbers of subjects. Thus, we propose to conduct the largest (to our knowledge) controlled trial to date, of the calcium channel blocker verapamil, in bipolar manic patients who were unresponsive to four weeks of initial treatment with lithium. Medication will be administered under double-blind, random assignment conditions. A group assigned to continued-lithium administration will serve as a control for possible confounding effects due to stage of illness, insufficient duration of initial treatment, or spontaneous cycling out of mania. The specific aim of this investigation is to assess the acute treatment efficacy of verapamil for treatment-resistant mania. Based on this aim we will pursue two primary hypotheses: 1) the proportion of manic subjects who respond to acute treatment with verapamil will be significantly greater than the proportion who respond to continued-lithium treatment; and 2) the mean change in Bech-Rafaelsen mania ratings produced during verapamil treatment will be significantly greater than the corresponding change produced during continued-lithium treatment. We will also pursue a secondary hypothesis: 3) the need for adjunctive lorazepam (administered on a prn basis) will be greater in the continued-lithium group as compared to the verapamil group. Eighty eight subjects (two groups of 44 each) will be randomly assigned to treatment with verapamil or continued-lithium for four weeks. We anticipate that a maximum of 20% of patients will be withdrawn from the acute phase of the study due to reasons such as intolerable adverse effects or withdrawal of consent. Thus, we expect the entered sample to yield 35 completed subjects per cell. This sample size will allow for adequate statistical power to test the hypotheses stated above.

Lithium remains the most effective medication in the management of bipolar disorder. This agent often causes a variety of side effects leading to its discontinuation and/or to a high rate of noncompliance. This study is a double-blind controlled study of oral inositol for amelioration of lithium-induced side effects. This preliminary investigation is designed to examine a wide range of side effects in order to identify potential targets for inositol action.