Reply to Hector Warnes’ comment by Barry Blackwell

Barry Blackwell: Lithium Controversy

Barry Blackwell’s reply to Hector Warnes’ comment.

Hector Warnes’ comments raise several important issues with some of which I take exception.

He begins by considering it “unfair” to compare Linus Pauling’s “orthomolecular excesses” with Schou’s advocacy for lithium.  This mistakes the intent of my comment, which was not to disparage Mogens but to point out that the validity of an individual’s scientific claims cannot be based on their reputation, above the accuracy and lasting value of the data they present. Even the most distinguished scientist, like Pauling, may have feet of clay on a particular topic. One has only to consider the lack of any lasting scientific value to the Nobel Prizes awarded for lobotomy and the catecholamine hypothesis, neither of which, in hindsight, burnished the hopes or reputations of their distinguished progenitors.

We agree entirely on the as yet unraveled complexity of exactly which subdivisions of bipolar disorder do well on lithium and why. But a reduced propensity for suicide in some of those treated with lithium does not necessarily constitute an “anti-depressant effect”.  Full blown manic disorders with agnosia create sufficient havoc in the domestic and professional lives of those who suffer that a lithium induced return to sanity might well be sufficient to stifle an existential desire to “end it all’.  Where we do agree is that episodes of covert and unrecognized hypomanic behavior may masquerade as ‘recurrent depressive disorder’ and erasing these with lithium may have an unexplained effect on the natural history of such disorders. One thing clear to almost everybody prescribing lithium to bipolar disorder is that it does not benefit depression and that a search continues to find a drug that does so without triggering mania.

This brings me to Hector’s final point about imipramine, which also misrepresents my view.  Baastrup and Schou’s original study displayed the natural history of each patient’s disorder. It was clear that some individuals had recurrent depression without manic episodes. In the mid 1960’s, imipramine was just coming into widespread use, which led us to speculate these depressed individuals might respond equally well to an antidepressant. This proved to be the case in patients selected from the Maudsley data base with no bipolar history, applying the same flawed statistics which favored spontaneous remission in a recurrent disorder treated at its peak. We only learned later that our patients were not the same as those treated by Schou who, like his brother, had already failed to benefit from imipramine and may have had an occult bipolar diathesis. This distinction was confirmed by the NIMH Study Group project (Prien et al, 1984), which found imipramine preferable to lithium for long term preventative treatment following recovery from an acute episode of unipolar depression.

Where Hector and I most agree is on his selective use of lithium and the philosophy that underlies it.  Faced with a culture devoted to polypharmacy and a flexible consensus-driven nosology, his choice of patients and close attention to treatment monitoring reflect the ideals pioneered by Trautner and Gershon, later appropriated by Cade with cursory acknowledgment.

In between these issues, Hector cites a laundry list of neuroscience studies (references not given), suggesting lithium has putative effects on “neurotransmitters, neuronal activity and genetic expression,” findings he alleges no longer allow us to be “strictly Kraepelinian”. The problem is that a diversity of unrelated findings leads us nowhere in our current state of abysmal ignorance about how the brain functions. A very recent op-ed in the New York Times by Gary Marcus, a neuroscientist, (“Gray Matter”, June 28, 2015) describes the difficulty of assigning meaning to isolated findings, “Science has a poor track record when it comes to comparing our brains to the technology of the day. Descartes thought that the brain was a kind of hydraulic pump, propelling the spirits of the nervous system throughout the body. Freud compared the brain to a steam engine. The neuroscientist Karl Pribram likened it to a holographic storage device.”  His own attempt to promote a novel computer technology (Field programmable gate arrays) leads to the following conclusion, “It is unlikely that we will ever be able to directly connect the language of neurons and synapses to the diversity of human behavior, as many neuroscientists appear to hope. The chasm between brains and behavior are just too vast…There is much we don’t know about brains. But we do know they aren’t magical. They are just exceptionally complex arrangements of matter”.

Those of us who explore the historical enigmas of our specialty with its controversies and contradictions must also learn the lessons of parsimony and humility.


Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Arch Gen Psychiat 1984; 41 (11): 1096-104.


Barry Blackwell
September 24, 2015