Schildkraut

Drawing all this evidence together, Schildkraut (1965) concluded that depression was caused by a functional deficit of noradrenergic transmission in the brain. He also thought that the rebound depression and fatigue, which are experienced after the arousing effects of amphetamine have worn off, were due to depletion of neuronal stores of noradrenaline. However, Schildkraut made a clear distinction between the effects of antidepressants and the arousal induced by amphetamine, describing the latter as stimulation and excitement . To this day, there is controversy over whether or not amphetamine has a beneficial effect in depression. 

A logical conclusion from this work was that depression is caused by hyperresponsive )S-adrenoceptors. At first, this might seem to undermine Schildkraut s suggestion that depression is caused by a deficit in noradrenergic transmission. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, dowmegulation of jS-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. 

Schildkraut, JJ (1965) The catecholamine hypothesis of affective disorders a review of supporting evidence. Am. J. Psychiat. 122 509-522. 

Although we must await further clarification, a large number of genes have already been identified to exert major influences on therapeutic targets response to psychotropics (Schildkraut, Kopin et al, 1995). These include genes encoding transporters and receptors of key neurotransmitters believed to be involved in... 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

The re-examination of the clinical reports showing that most people who were given reserpine did not become depressed was not published until 1971, a few years after the chemical-imbalance theory had been popularized by Schildkraut and Coppen. But a decade before their influential articles were written, there had been a carefully controlled clinical trial on the effects of reserpine on mood.17 Far from confirming the belief that it made people depressed, the study seemed to show the reverse. Rather than making healthy people depressed, reserpine seemed to make depressed people better. As described by Michael Shepherd, the senior author of the study, in 1956 ... 

Schildkraut and Coppen should have known that reserpine inhibited the reuptake of norepinephrine and serotonin, because... 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

Schildkraut, Joseph J., The Catecholamine Hypothesis of Affective Disorders A Review of Supporting Evidence , American Journal of Psychiatry 122 (1965) 509-22... 

Newman M, Strzelecka T, Dorner LF, Schildkraut I, Aggarwal AK (1995) Science... 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

P. Doty, J. Marmur, J. Eigen, and C.E. Schildkraut, Strand separation and specific recombination in deoxyribonucleic acids physical chemical studies. Proc. Natl. Acad. Sci. 46, 461-476 (1960). 

Schildkraut, D.E. 1993. Application of analytical voltammetric methods to the determination of silver at sub-ng/mL levels. Pages 5-7 in Andren, A.W., T.W. Bober, E.A. Crecelius, J.R. Kramer, S.N. Luoma, J.H. Rodgers, and A. Sodergren (organizers). Proceedings of the First International Conference on Transport, Fate, and Effects of Silver in the Environment. Univ. Wisconsin Sea Grant Inst., Madison, WI. 

Schildkraut, D.E., P.T. Dao, J.P. Twist, A.T. Davis, and K.A. Robillard. 1998. Determination of silver ions at submicrogram-per-liter levels using anodic square-wave stripping voltammetry. Environ. Toxicol. Chem. 17 642-649. 

Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methyl-paratyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central... 

Horton, N. C., Domer, L. E, Schildkraut, I. and Perona, J. J. (1999). Crystallization and preliminary diffraction analysis of the FlincII restriction endonuclease-DNA complex. Acta Crystallogr. D 55,1943-1945. 

Newman, M., Strzelecka, T., Domer, L. F., Schildkraut, I. and Aggarwal, A. K. (1995). Structure of BamHI endonuclease bound to DNA partial folding and unfolding on DNA binding. Science 269, 656-663. 

Viadiu, H., Kucera, R., Schildkraut, 1. and Aggarwal, A. K. (2000). Crystallization of restriction endonuclease BamHI with nonspecific DNA. J. Struc. Biol. 130, 81-85. 

The content of guanine G and cytosine C of double-stranded DNA is calculated from density according to Schildkraut et al. ... 

Cassens G, Kuruc A, Roffman M, Orsulak P, Schildkraut JJ (1981) Alterations in brain norepinephrine metabolism and behavior induced by environmental stimuli previously paired with inescapable shock. Behav Brain Res 2 387-407... 

Schildkraut, J., Green, A., and Mooney, J. (1989) Mood disorders biochemical aspects. In Kaplan, H. and Sadock, B., eds. Comprehensive Textbook of Psychiatry, Baltimore Wilkens Williams Vo/. I. pp. 868-879. 

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