New Concepts

Since the early 1950’s, Samuel Gershon, M.D., has questioned the neurotransmitter receptor concepts concerning the mechanism of action of antidepressants and the etiology of depressive disorders.  This was in part motivated by the observation that lithium, which has no direct effect on neurotransmitter receptors, had anti-manic, anti-depressive, and prophylactic activity in depression.

A different conceptual approach for major neuropsychiatric disorders, including depressive disorders, has been the subject of almost 3 decades of research by Jay W. Pettegrew, M.D.  This concept is that there is nothing structurally wrong with neurotransmitter receptors, but the receptors are in a membrane environment that has altered molecular structure and dynamics.  It is these membrane lipid alterations that alter the functional dynamics of neurotransmitter receptors which in turn alters their physiological function.  We recently demonstrated that by altering the structure and dynamics of a model membrane, the structure and dynamics of the embedded protein was clearly altered (Mandal and Pettegrew, 2004).  In addition, a recent study demonstrated that the molecular dynamics of a protein were important for its normal enzymatic function (Eisenmesser et al., 2005; Haung and Montelione, 2005). Dr. Pettegrew was one of the first to demonstrate alterations in membrane molecular dynamics in living cells obtained from patients with neuropsychiatric disorders including depression and bipolar disorder (Pettegrew et al., 1979b,c; 1980a,b; 1981a,b; 1982b; 1987b; 1988c; 1990b,c; 1993a,b).  Dr. Pettegrew demonstrated that lithium can correct the membrane dynamic alterations observed in bipolar I depressed and manic patients suggesting a mechanism for lithium’s therapeutic effect.

Given the rather striking changes in membrane molecular dynamics, Dr. Pettegrew turned to investigate alterations in membrane phospholipid metabolism (Cohen et al.,1984; Geddes et al., 1997; Glonek et al., 1982a,b; Kanfer et al., 1993; Keshavan et al., 2003; Klunk et al., 1996; 1998; Pettegrew et al., 1978; 1979a; 1981; 1982a; 1986; 1987a; 1988a,b,c; 1990a; 1991; 1995; 2001; Singh et al., 1994; Sweet et al. 2002) and again significant alterations were observed in several neuro-psychiatric disorders including geriatric depression (Pettegrew et al., 2002).  Again, lithium was shown to correct the alteration in membrane metabolism observed in patients with depression providing more evidence for the membrane concept for depressive disorders (Pettegrew et al., 2001).