Arnold j. Mandell

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ARNOLD J. MANDELL

Interviewed by David Healy

Las Croabas, Puerto Rico, December 13, 1998
DH: My name is David Healy and today is the 13th of December 1998. I’m interviewing Arnold Mandell, today, on behalf of ACNP. Arnold was one of the early pioneers in the field, a man of fun and genius, but unconventional genius, I think. Arnold, can we begin with how you came into the field? Well, let’s go back to where you were born and brought up.

AM: I was born in Chicago. My mother was a Chicago Conservatory pianist and piano teacher and my father was saxophone and clarinet playing jazz musician and band leader. My mother taught me and pushed me to study classical music. My father used records and stories to interest me in jazz. He had hung around in the Chicago jazz crowd with pioneer, Earl Hines, “the father,” and his crowd, which sometimes included Ellington, and had written a piano book with him. So, my childhood was dominated by a tug-of-war between classical music and jazz. As an adult, a similar struggle dominated my work; between psychoanalysis and brain biology.

As I was growing up, practicing three to four hours a day, it was seen as virtuous to work at Bach’s Two and Three Part Inventions, and “dirty” to improvise around “I Got Rhythm”. I remember writing an arrangement entitled “How High the Moonlight Sonata”, which my mother hated. In my early teens and then on, I settled on a piano style that was most like that of Oscar Peterson and tried, but failed, to be Charlie Parker on the saxophone. I, however, did win several American Federation of Musicians contests on classical music for the alto sax.

I have always heard patient’s stream of associations like jazz improvisation, with the person’s character revealed in the style of their flow of talk. Schizophrenic discontinuity and thought disorder “swing” like Thelonious Monk. Then, there was the plaintive obsessive ruminations of Bill Evans; the manic flight of Art Tatum; the psychopathy of Bud Powell. In 1997, I gave an invited address at the Fourth Experimental Chaos Conference, in which Karen Selz and I used dynamical systems’ ergodic theory to quantitatively differentiate between nonlinear measures of a variety of modern jazz styles, as well as early versus late Beethoven. The styles were clearly and quantitatively discriminable.

I got interested more directly in the brain in my early teens when my dad gave me a book from the early 1900s by Roger Blatchford, called Not Guilty. It concerned the social psychology of criminality. It developed the position that most people weren’t voluntarily evil, but, rather, their style of behaviour was the result of the interaction of the genetics of their brain and the influence of their environment during growth and development. About the same time, he also gave me an early 1930s book on physiological psychology of the brain. It was a very primitive book that discussed among other things, the shapes and bumps in the head in relationship to a person’s immutable behavioural patterns.

DH: A point of view that’s old, but lost now, isn’t it, the notion of the influence of physical constitution?

AM: Well, on one hand it’s lost and on the other hand, the same set of assumptions underlies much of our current theories of genetic inevitability; somatotype has been transformed into nucleotide sequences and proteomic expression with the same “anatomy as destiny” kind of finality. When I went to Stanford, having been a brain groupie during my teens, I was really disappointed to find that there were no laboratories of neuroscience or neuropharmacology.

DH: Nothing. You actually went to Stanford in 1958?

AM: No, I was seventeen and entered Stanford in 1951. I majored in psychology and chemistry, and spent my extra-curricular time running rats for professors in Stanford’s psychology department, especially for D.H. Lawrence, and working on the unfolding of neural crest tissue to become autonomic ganglia in the embryology laboratory of Graham Dushane. He was very scholarly and quite influential in my life, somehow teaching me the transcendent feeling of the doing of research. He was editor of Science for several years.

I was encouraged to frame the rat data so I was getting in the language of mathematical learning theory of the sort being talked about by Sid Siegel, the nonparametric statistical whiz, and Richard Atkinson, later Chancellor of UCSD in La Jolla, and then all campuses at University of California. I was remarkably lucky to have close relationships with these men and other senior post-docs and junior faculty in psychology at Stanford.

I got to be present and participate in discussions late into the night in front of blackboards borrowing chemical kinetic equations to represent learning functions, comparing the drive reduction theories of Hull and Spence with the operant theories of B.F. Skinner and his followers. I also continued to maintain my interest in the anatomy and physiology of the brain for which I was frequently teased by these radical behaviourists.

I also had a memorable semester in a private tutorial with Albert Bandura, reading Otto Fenichel’s The Psychoanalytic Theory of Neurosis. In my third and final year at Stanford, John Eccles’s The Neurophysiological Basis of Mind came out, which made learning functions neuroanatomical and observable even in the spinal cord. I carried the books of Eccles and Fenichel around for years. Maybe it should be noted, relative to my later life, I also fell in love with and took courses in organic chemical reaction mechanisms. I guess I was trying to find some kind of harmony in the aggregate of mathematical, psychoanalytic, neuroscientific and organic chemical thinking. This search for accord became the signature of my inner life, but was already in place in primitive form at Stanford in 1951 and 52. It was also the framework for a lifelong conflict that remains unresolved.

DH: Conflict?

AM: Well, let me begin by saying that I spent close to ten years as a patient, called “candidate,” in four times per week psychoanalysis. My first psychoanalyst, when I was at Tulane Medical School in New Orleans, was the New Orleans Institute training psychoanalyst, Irwin Marcus. Later, during my residency at the Neuropsychiatric Institute at UCLA, I entered training psychoanalysis in the Southern California Psychoanalytic Institute, and spent five years with Judd Marmor.

During my first psychoanalysis, in New Orleans, I worked nights and weekends doing spinal cord research in cats under oil in the Physiology Department directed by Matt Bach, an early student of Horace Magoun, of reticular formation fame. The work itself was inspired in part by John Eccles and in part by Horace Magoun, especially the 1951 symposium, Brain Mechanisms and Consciousness, edited by Jasper.

I also spent a couple of years around Robert Heath and his group watching him use depth electrodes in the human septal region for stimulation in schizophrenics. He focused on the inability of chronic schizophrenic to experience pleasure: anhedonia. Septal stimulation was found to be pleasurable to these patients. They were outfitted with stimulus boxes on their belts so they could dose themselves as needed. Heath’s group also was extracting plasma from schizophrenics looking for what he believed to be a unique protein fraction, something he called taraxein.

Heath was the reason I had gone to Tulane in the first place. He had promised me a place in his laboratory. He looked like Gary Cooper, and his charisma and easy familiarity with both brain biology and psychoanalysis were really seductive. His background participating in the Columbia-Graystone Project, involving selective cortical and limbic ablations in chronic schizophrenic patients as well as his psychoanalytic training under Sandor Rado made him a living representative of my fondest dreams for myself. Nonetheless, I found his laboratories too intimidating once I got there, so after a year or so, I switched to the uptown physiology department, under the supervision of L.M.N. Bach.

I published my first scientific paper in 1956, comparing brain stem descending and local spinal cord inhibition and their interaction in the lumbar spinal cord in the anesthetized cat. My second paper, delivered at the Fall Meeting of the American Physiological Society of that year, reported a relationship between medial bulbar sites eliciting descending motor inhibition under anesthesia and the same site in the awake cat generating fear behaviour, and lateral bulbar sites eliciting motor facilitation under anesthesia and out of anesthesia, pleasure, indicated by languorous purring.

In those days there was a great deal of tension between “biological psychiatry” and “dynamic or psychoanalytic psychiatry”. My fellow psychoanalytic candidates and some of the teaching analysts told me directly that I couldn’t be a real psychoanalyst and a biological brain researcher at the same time; that I had to choose. It would be considered silliness now but it was an issue full of rancor in those days. Biological Psychiatry was considered a “resistance” to psychoanalytic insight by many. The issue came to crisis during my psychiatric residency at UCLA’s Neuropsychiatric Institute.

DH: What happened?

AM: I was in the same conflictual position again. On one hand, I was getting analyzed four times per week with Judd Marmor, and spending four hours a week in Southern California Psychoanalytic Institute seminars. On the other hand, the Brain Research Institute space committee gave me the laboratory that had belonged to the psychopharmacology pioneers, Eva and Keith Killam, who had transferred from UCLA to UC, Davis.

From seed money and some NIH and State Mental Health Funds, I developed a biochemistry laboratory that studied the interactions of human limbic stimulation with corticoid release and plasma levels. We collected several times per week and several times per day, urinary corticoids and tryptophan metabolites in bipolar patients, and, studied the effects of elevated plasma and urine corticoids on tryptophan metabolism in man. Following some early animal work on hepatic enzyme induction with corticoids by Knox and his group at Harvard, my team, particularly Irene Mersol Sabbot and Robert Rubin and the clinical staff of my Neuropsychiatric Insitute in-patient unit, collected urine every six hours for weeks in urinary time series in starving patients and in patents with disordered affect.

We published several papers reporting our story, principally about the metabolic evidence of the induction of hepatic tryptophan pyrolase activity in depression associated with elevated urinary corticoid excretion, and the cleavage of the indole ring leading to marked reduction in peripheral serotonin metabolites, one of which I reported in man for the first time. I got the Society for Biological Psychiatry’s A.E. Bennett Prize for this work. This finding was indirect evidence of a possible brain serotonin deficiency in affective disorder. Ed Sachar, at Einstein, and Biff Bunney, at NIMH, were also following steroids in affective disorder found a peak in depression.

My fellow analytic candidates in Southern California at the time called me “the urine boiler”. They teased me about trying to understand the human soul through the kidney. I just didn’t want any more of what was sounding more and more like a fundamentalist religion. I finished my training analysis with Marmor, who was supportive of my biological research life, treated two training clinic patients classically analytically under supervision - three were required for institute membership - and attended analytic seminars for five years. One day I decided I had had enough.

When I resigned from the Institute, several of my candidate and analyst friends told me that no one would believe that I had resigned. They insisted that everybody would assume that I had been thrown out. That fixed it for sure. I was finished. Beyond what I had done, it seemed a waste of time. It got less and less relevant to my clinical interests, and I was finding the brain relevant research increasingly exciting. I wanted to chase the serotonin story into the brain. In addition, around that time, I had several critical clinical incidents that led me into psychopharmacology.

DH: What were the incidents?

AM: I guess the issue can be captured in two stories. The first story was during my residency when I was doing several months of daily psychotherapy with an in-patient. She suffered from what was known in those days as “involutional depression”, which rode on an obsessive-compulsive, passive-aggressive character. She was getting worse and worse every day. Although the supervisor recommended shock treatment, I was in analysis and in psychoanalytic seminars and wanted to see what I could do with insight. They agreed to let me keep her in the NPI hospital for months to try. The patient was the unmarried older sister of a bookkeeper. She was the caretaker of her aging mother, and in her early fifties she began to lose sleep and weight, experienced a marked increase in her obsessive-compulsive traits and became suicidal.

My psychotherapy was about her unconscious frustration and rage; her resentment of her sister, and mother, for stealing her life from her. This treatment appeared to be making things more painful for her. She, of course, felt accused, but denied it all and the talk only made things much worse. All the while she continued her passive aggressive praise of me for making her so much better. I was growing desperate because I didn’t want to use ECT, but saw it as inevitable.

It was at this time, in 1960 that I got a drug from a detail man, a new Ciba-Geigy drug, imipramine-Tofranil. It was initially thought to be antipsychotic, but was showing antidepressant actions. I will never forget the third day of her treatment with imipramine. I was late for the daily visit, and when I entered her room, she looked at me with obvious irritation, for the first time, and said, “You’re late”. She had never been able to speak to me, or I think almost to anyone, like that. In the next three weeks, her syndrome of over two year’s duration disappeared! Her sleep and appetite returned; her delusions of “smelling bad” and “contaminating the chairs if I sit down” were gone. She was easily able to speak about her “boxed in” state and began to make new life plans for herself.

From a dynamical point of view, imipramine reduced her separation anxiety - Don Klein developed this thinking most clearly - which trapped and unconsciously enraged her; her felt anger made her feel like a “bad person”. She described how happy she was with her new “freedom to choose”. That was my neuropsychopharmacological moment! I saw that not only symptoms but permanent characterological features of a person could be changed with these new psychopharmacological agents. Who a person was could be altered; not tranquilized, not muted, not speeded, but changed in fundamental ways such that the “new person” was not capable of manifesting the presenting illness.

It was about this time that I began a long lasting and close relationship with Nathan Kline, known for his pioneer work with reserpine and monoamine oxidase inhibitors. Nate’s real greatness was in the intimate observations he made on the patients he was treating with drugs. When we talked, it was inevitably about how the drug influenced subtle aspects of the whole person, his fantasy life, his sexuality, ambition, aesthetic tastes and appetites, and subtle aspects of the therapist-patient interaction.

Our relationship lasted until his death in the late 1970’s. Nate was known as a wild, drug wielding, cowboy. What most people didn’t know about Nate was his subtle, highly personal, psychodynamic view of psychotropic drug actions. He saw his drug treatment patients over significant amounts of time using long term follow-ups.

People came from all over the Country to see him. He was a marked influence on how I practiced psychiatry. When I would notice a drug induced change in a person, even not relevant to his presenting disorder, say lithium reducing the obsessive urges to gamble or binge drink, I would call and talk to him about it. We spoke about lithium “slowing down” internal processes sufficiently to allow good judgement to play a role in its effect. I always took him seriously, even literally, and he was usually right. For instance, I studied lithium effects on brain enzyme kinetics, and made some computations concerning measures of diffusion in lithium-structured water; all of it pointed to a “slowing” as a global phenomenon.

For the rest of my professional life, I thought of effective psychopharmacological treatment as changing a person into someone else who was less vulnerable or even incapable of having the psychiatric disorder with which they had originally presented. I saw, and see, drugs as altering the defense pattern and strength of the person, and that this, secondarily, becomes therapeutic with respect to the patient’s diagnosis. There must be a psychobiology of character and its changes.

During my stay at UCLA in the early and middle 1960’s every patient got an MMPI and therefore a characterological profile. I watched drug treatment change the “shape” of the MMPI profile, particularly in the Axis II characterological scales. Tricyclics reduced or eliminated the MMPI profile of a ruminator. Low doses of antipsychotic changed the Sc-Pd MMPI profile, called, but not really, “schizoid-psychopathic” character. Anti-epileptics changed the threshold of the hysteroid-impulsive ego disruption of the Hy and Hs (hypochondriasis) parameters. Acute changes in anxiety, Pt (psychasthenia) and D (anxiety, depression) were to be expected, but changes in indices of long term character patterns were not. Many wonderful studies by others have since supported this kind of thinking since those early, “pre-scientific” days. Like Chinese medicine, rather then emphasizing DSM-III Axis One catalogued primary symptoms, I was always most aware of the Axes Two dimension, the patient’s character and personality and let these variables play a significant role in drug choice and dose.

This theme found its way into my neurobiological research, as well. Our laboratories focused on long lasting psychotropic drug induced changes in long lived macromolecular reflections, such as the neurotransmitters’ rate limiting biosynthetic enzymes and the sensitivity state of the relevant receptors, as representative of characterological states. These were the changes invoked by chronic administration of antidepressants and antipsychotics in experimental animals, and I viewed these changes as the neurobiological correlates of characterological change.

The second story is more about the state of psychiatry in the early 1960s. I went to my first American Psychiatric Association meeting and also to the meetings of the Society of Biological Psychiatry and of the American Psychoanalytic Association. Once, at a luncheon with the biological psychiatrists, I just happened to be sitting across the table from a very thin, bearded, threatening looking man in his late fifties who described his current research project as doing “ice pick lobotomies” on “acting out adolescents”. This was, as I later learned, my first contact with Walter Freeman, the major protégé of the Portugese Nobelist, Antonion Moniz, who invented the lobotomy.

Terrified, I ran across to the Waldorf Hotel where I thought the psychoanalysts were meeting. Breathless, I entered a big meeting hall and found a seat in the corner. Lo and behold, the man in front was speaking Yiddish. Since I knew that there was a heavy Jewish membership in the psychoanalytic societies, I wasn’t surprised, at least for a little while. I was sitting there, uncomprehending, for about twenty minutes before I saw a sign in the corner that said B’nai B’rith. It was a meeting of the Jewish advocacy group, not the American Psychoanalytic Association! So that was what a brain groupie was faced with in the late 1950’s and early ‘60s. A choice between lobotomies or a Jewish fellowship!

DH: Were you teaching then?

AM: Yes, as a NIMH Career Teacher Awardee in 1962, I developed the first undergraduate medical school course in clinical psychopharmacology at UCLA. It was a three-week course, taught within the psychiatry block in the third year. For drug indications, their mechanisms and their effects I combined two points of view: neurobiological mechanisms of action that included biogenic amine dynamics, limbic system function etc. the basis for which was taught by Wallace Winters and Charles Spooner in the Pharmacology Department, and a psychoanalytic view of personality and character. Much of the clinical material was from my own Beverly Hills-Brentwood practice, which I maintained for about 40 hours a week with a full Saturday, done after 4:00 PM each day.

It was the early 1960’s and I was doing dynamically oriented psychotherapy along with psychopharmacology. I saw each patient one, two, or more full “fifty-minute” hours a week with or without drugs. The current practice, the very short time spent by psychiatrists with patients, using powerful drugs that make major global changes in personality, most of which they are unaware, is upsetting to me. These powerful drugs influence so much of a person’s inside and outside reality, and so little of what is being changed is being observed by the psychiatrist. I see it as insurance plan supported very bad practice.

DH: What do you mean by psychopharmacology from a personality dynamics point of view?

AM: I actually talked about it for years and wrote about it for Judd Marmor’s recently republished book, called Modern Psychoanalysis. I called it “dynamic psychopharmacology”. I was talking a lot at that time with Donald Klein, of similar bent, who was studying the relationship between personality type and drug responses. For example, Donald Klein described two different drug responsive anxiety syndromes.

Many others were also working in this area. For example, DiMascio and Gerry Klerman described the poorer response of hyper masculine types to non-motor activity promoting phenothiazines, such as Thorazine, compared with Stelazine (trifluoperazine). Of course, the new antipsychotics, with considerably less extrapyramidal influence mitigate this difference. A “fat and sleepy” depressed person responded better to monoamine oxidase inhibitors, and the “thin sleepless” depressed person was more responsive to the tricyclic agents, such as Tofranil.

I insisted on once, twice or more a week of close clinical, full hour attention to patients on psychopharmacological agents, from my senior residents. This yielded regular discussions of the subtle and global personality properties of the drug response. Mortimer Ostow continued psychoanalysis with patients taking psychotherapeutic agents and spoke of descriptors such as the amount of “extrapyramidal libido”. He spoke of titrating psychic energy using blink rate.

I was convinced that the tricyclics reduced inertia and facilitated action in depressed patients, so I extended the observation. In 1962, I published several papers with evidence that Parkinsonian rigidity and inertia, not tremor, was almost completely mitigated by tricylic antidepressants. I called it “Motivation and Ability to Move”. The neurosurgeon, Robert Rand, at UCLA said that previously poor prognosis Parkinson patients on tricyclics became good candidates for surgery, having lost their rigidity which was not subject to improvement by pallidectomy. About the same time, I also worked with Rand and Robert Rubin, my students, to show that simulation of the amygdala in their electrode implanted temporal lobe epileptics increased plasma and urinary corticoids, while hippocampal stimulation reduced plasma and urine levels. In my course for medical students I was speaking of amygdala fear and rage and hippocampal peaceful transcendence.

I commuted to Boston once a year or so to attend Normand Geschwind’s clinic and shared dinner with Harvard’s neurology professor - who should have shared Sperry’s Nobel Prize for his theories of hemispheric “disconnexion” syndrome - and spoke with him about his remarkable collection of temporal lobe syndromes. His transcendent, asexual right lobe syndromes reminded me of St. Paul and some of the phenomena I experienced during the effects of LSD, which I obtained for personal experimentation from Barbara Brown at the Los Angeles VA Hospital. I was immersed in Barbara Meyerhoff’s studies of the Hiuchol Indians who took Peyote with their ritual practices. I was also one of Sacha Shulgin’s human subjects when he was developing the methoxy- and halogenated-amphetamine series, one of which is Ecstasy.




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