An assessment of the catecholamine hypothesis of bipolar disorder

Catecholamines - dopamine, norepinephrine, and epinephrine - are a class of endogenous compounds fundamental to the neurological, psychiatric, endocrine, and cardiovascular functions of the human body. In the mid-1960s, there emerged a catecholamine hypothesis of bipolar disorder (CHBD) amidst pharmacological observations that drugs with catecholamine-enhancing properties elevated mood while catecholamine-depleting agents caused depression (Rosenblatt et al., 1960; Bunney and Davis, 1965; Schildkraut, 1965). Subsequent iterations of the CHBD have strayed from the original, primarily with regard to which catecholamine is associated with which mood state, but the central principle has not changed: namely, that the two clinical poles of bipolar disorder - mania and depression - result from functional changes in the activities of catecholamines, with low activity causing the depressed state and high activity the manic state (Randrup et al., 1975; Serra et al., 1979; Bunney and Garland, 1982; Berk et al., 2007). In this chapter, we begin by reviewing the historical context in which catecholamines came to be discovered and modern conceptions of their biochemistry. We then assess the validity of the central principle of the CHBD through a systematic discussion of work spanning over 60 years. Lastly, we share our perspective on the role of such “single neurotransmitter, single disease” hypotheses in future psychiatric research. The discovery of the catecholamines In 1856, Vulpian, a French neurophysiologist, applied a solution of ferric chloride to slices of mammalian adrenal glands and noticed that the medulla stained green while the cortex did not. The same reaction occurred in samples of venous blood leaving the adrenal, but not in the arterial blood entering the gland, leading him to conclude that the medulla synthesized an unknown substance circulating throughout the body (Vulpian, 1856). Forty years later, George Oliver, a rural medical practitioner, and Edward Schäfer at the University College of London reported that adrenal extracts possessed pharmacological properties when they observed a rise in arterial blood pressure after administration to a dog (Oliver and Schäfer, 1895). The therapeutic implications of this finding stimulated a search for the active component of the extracts, and 2 years later John Abel and A.C. Crawford (1897) claimed to have identified the component. Their extract - which they called “epinephrine” - did not exhibit the strong physiological activity of the cruder versions, thus efforts to isolate the active component continued.