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Wednesday, 28.10.2020

Bernard Lerer: From Freud to Biology, From Genes to Medicines: A 40-Year Perspective*

 

"Much have I learnt from my masters,

more from my fellow students,

and from my disciples, most of all"

Babylonian Talmud, Makkot, 10.1

 

        My 46 years in psychiatry, from 1974 to the present, have coincided with the rise of biological psychiatry and psychopharmacology. In this time, psychiatry has become a scientific discipline with neuroscience as its basis and techniques such as molecular genetics and neuro-imaging key instruments of research inquiry. We are seeing pivotal developments in the field of brain stimulation and a major thrust to apply big data analytics to transcriptomic and also clinical and demographic data.

        This is a personal perspective on the 46 years I have spent in Israeli psychiatry with emphasis on the development of biological research, the individuals who were key figures in this process and my own career. This is not a scientific review nor a systematic history but a personal story of an exciting period and the remarkable people who made it so.

 

Beginnings in medicine and psychiatry: 1966-1977

 

        I had the privilege of studying medicine at the University of Cape Town, South Africa, and graduated from UCT Medical School in 1971 at the age of 23. The first heart transplant was performed at Groote Schuur Hospital in Cape Town by Christiaan Barnard while I was a student there. I had a fantastic clinical education in the British tradition. As a result, I spent a year in internal medicine at Hadassah Medical Center in Jerusalem before eventually switching to psychiatry. Yaakov Avni was my first clinical supervisor in psychiatry. He was a skilled clinician and a dedicated mentor. He had just returned from a research fellowship in Boston with the renowned Joseph Schildkraut, formulator of the catecholamine hypothesis of affective disorders. Most of what I know about clinical diagnosis in psychiatry, I learned from Yaakov. He also introduced me to the connection between depression and the thyroid gland, which would become central to my research career.

        My first encounters with patients are indelibly impressed on my memory and had a major effect on my thinking about psychiatry. I vividly recall a so-called “hebephrenic schizophrenic” who was my first ever patient. My encounter with her was enough to convince me that schizophrenia, contrary to what was widely believed then, had to be a disease of the brain. I was not the first but it took a while for the whole psychiatric world to be convinced.

        An important visitor to the Hadassah Department of Psychiatry in 1974 was Herman van Praag who came from Groningen in Holland. Herman spent a sabbatical at Hadassah and gave us an unforgettable course on biological psychiatry and psychopharmacology. He was one of the first people to intensively study the connection between serotonin and depression. He had a major impact on the field and on me personally.

 

Encounter with psychoanalysis: 1975-1978

 

        I studied at the Israel Institute for Psychoanalysis in Jerusalem from 1975-1978. It was a formative experience, enriched by the excellent, if sometimes dogmatic, teachers we had. The teacher I remember most vividly is Erich Gumbel, an orthodox psychoanalyst who was systematic and inspiring. I graduated from the three-year psychotherapy course and proudly display the certificate in my office. There is no doubt that what I learned at the Psychoanalytic Institute influenced me a great deal in my clinical practice. Psychiatrists have drifted away from psychotherapy in the last 40 years and in so doing have lost the key clinical insights that this discipline provides. I was taken with psychoanalytically-oriented psychotherapy but could not live in peace with its exponents. It irritated me that they had answers to everything and most of the answers had to do with resistance. In 1979 I wrote an article in the Israel Annals of Psychiatry and Related Disciplines in which I put forward my views and criticisms (Lerer 1979). I wrote: “Psychoanalytically oriented psychotherapy is a long and time-consuming process. Neither its end-point nor its goals are universally defined. Too often both seem arbitrary and malleable...” (Lerer 1979).

 

Ezrath Nashim – Crucible of Israeli Biological Psychiatry: 1977-1982

 

        My first real steps in Biological Psychiatry were taken in 1977 at Ezrath Nashim Hospital in Jerusalem, now called Herzog Hospital. I went there to work with Robert (Haim) Belmaker who had taken over the laboratory originally founded by Elliot Gershon. Haim was doing translational research decades before the term was invented. The laboratory at Ezrath Nashim was a remarkable place that attracted an array of talented psychiatrists. Many went on from there to become leaders of Israeli psychiatry and pivotal research figures – Avi and Ronit Weizmann, Ehud Klein and Yossi Zohar, to mention only a few. I learned how to design experiments, how to work with laboratory animals and how to measure serum lithium levels using a flame photometer. I vividly remember the research seminars at which Haim would tell us about exciting developments like the Danish Schizophrenia Adoption Studies. I learned a great deal from Dick Ebstein and did a lot of work with him. More than a quarter of a century later, Dick went on to be the PhD adviser of my son Dr. Elad Lerer!

        My first full scale experiment in biological psychiatry dealt with the effect of the beta-2 adrenergic agonist, salbutamol, on depression and plasma cyclic AMP (Lerer, Ebstein and Belmaker 1981). Why salbutamol? Why plasma cyclic AMP? Because a trail-blazing paper in Nature by Vetulani and Sulser (Vetulani and Sulser 1975) had shown that antidepressants induced down-regulation of cortical beta-adrenergic receptor mediated adenylate cyclase in rat brain. This was thought to be a key mechanism of action of antidepressants. We showed that treatment with salbutamol, a beta-2 adrenergic receptor agonist, down-regulated the plasma beta-adrenergic-mediated cyclic AMP response to acute salbutamol infusion in depressed patients while significantly improving depression (Lerer, Ebstein and Belmaker 1981) – a translational research triumph in its time!

        From the start of my residency, I had been interested in ECT. I was fascinated by how effective the treatment was and intrigued by its unknown mechanism. I began to read widely on the subject and this led to an influential review paper with Haim Belmaker in Biological Psychiatry on receptors and the mechanism of action of ECT (Lerer and Belmaker 1982). I learned from that paper that if you have something interesting and potentially important to say, the scientific world will listen no matter how inexperienced you are. I participated in basic experiments on the mechanism of ECT and lithium and at the same time edited a book on ECT mechanisms with Belmaker and Richard Weiner of Duke University (Lerer, Weiner and Belmaker RH 1984). This was the beginning of a lifelong interest in biological mechanisms of psychiatric treatments (including ECT, lithium, antidepressants and anticonvulsants) that has yielded many published studies in both the basic and translational contexts.

 

Fellowship in Detroit – Carbamazepine and ECT: 1982-1984

 

        In 1982 I set forth with my family for Detroit for a post-doctoral fellowship with the legendary Samuel Gerson at Lafayette Clinic, Wayne State University. It was a truly remarkable period. Sam is one of the founding fathers of biological psychiatry and has had a huge influence on my career. To this day I consult with him on decisions of importance. As a mentor, he was a remarkable facilitator – he didn’t tell me what to do but gave me the conditions to do what I wanted while providing guidance and support. At the time reports of the efficacy of anticonvulsants in the treatment of bipolar disorder were beginning to appear. In Detroit I completed the first randomized, controlled trial of carbamazepine versus lithium in acute mania, showing equivalent efficacy (Lerer, Moore, Meyendorff et al. 1987). I also continued my studies on ECT mechanisms focusing on the role of brain muscarinic cholinergic receptors (Lerer 1985). For this work I received the A.E. Bennet Award of the US Society for Biological Psychiatry in 1984. I am indebted to the late Michael Stanley who was my mentor in the lab during the time I was in Michigan.

 

Ezrath Nashim - Focus on resistant depression: 1984-1990

 

        I returned to Israel in 1984 and went back to Ezrath Nashim. There, I set up a productive clinical research program with Baruch Shapira who was my resident and research collaborator. Together we established the first Resistant Depression Unit in Israel. We were able to help many seriously ill patients and did a great deal of research together. We received two successive NIH grants to study the optimization of ECT. This work yielded papers published in the American Journal of Psychiatry and British Journal of Psychiatry, in 1995 and 1998, respectively (Lerer, Shapira, Calev et al. 1995; Shapira, Tubi, Drexler et al. 1998). The critical finding, highly relevant to the neurobiology of ECT, was that the clinical effect of ECT is cumulative and gradual. It can be accelerated by increasing the frequency of treatments, but at the cost of more adverse effects and ultimately reaches the same endpoint.

        We also showed that caffeine pretreatment can be used to enhance seizures in patients with high seizure thresholds, clearly demonstrating this effect in a series of patients receiving ECT (Shapira, Lerer, Gilboa et al. 1987). Focusing on mechanisms, we used the neuroendocrine challenge approach that was popular at the time, to demonstrate the role of serotonergic mechanisms in ECT action (Shapira, Lerer, Kindler et al. 1992). Neuroendocrine challenge studies have been made redundant by PET imaging but in their time were a remarkably elegant translational research approach. At this time, I also implemented a series of experiments in the laboratory in collaboration with the late Michael Newman. This was the beginning of a long and highly productive association. Our work was focused on the mechanism of action of antidepressants, ECT and lithium and on the role of changes in adenylate cyclase activity (Newman and Lerer 1989a; Newman and Lerer 1989b).

 

Hadassah: Biological Psychiatry Laboratory 1990-

 

        In 1990 I moved back to Hadassah and set up the Biological Psychiatry Laboratory where I work until this day. Atara Kaplan DeNour recruited me. Atara was a true icon of academic medicine. She deeply valued the importance of research and realized that for research to be done effectively, the most precious commodity is time. She made sure that I had enough time to do research and encouraged the residents to work with me. Many did and several of them are now professors. They owe their achievements to Atara’s vision as much as to my mentorship. Her vision of academic psychiatry is a lesson that should be learned by all leaders of clinical, academic departments.

        Two people joined me in the move from Ezrath Nashim to Hadassah. Sadly, they are no longer alive and I miss them deeply. Michael Newman was an outstanding scientist with an NIH grant of his own. He was pivotal in setting up the laboratory at Hadassah. Rachel Alexander was a social worker who set up our family recruitment for genetic studies. She trained a generation of experts, among them Kyra Sarner-Levin, my research coordinator, student and collaborator for many years.

        The laboratory at Hadassah was soon functioning at full pace. We attracted a stream of outstanding PhD students to complement the talented psychiatrists who worked with us. I tried, like Sam Gershon, to be a facilitator and allow ideas to grow.

        As I returned to my basic research roots, we developed increasing expertise in biological models of psychiatric disorders. In 2014 this enabled us to win highly competitive support from the Israel Ministry of Science and set up Hadassah BrainLabs – the National Knowledge Center for Research on Brain Disorders – in partnership with Prof. Hanna Rosenmann of the Dept. of Neurology. It has been a productive initiative and a successful partnership.

        I owe the continuing success of the Biological Psychiatry Laboratory to many people but two are pivotal. Tzuri Lifschytz was my PhD student with Michael Newman. He is now the Laboratory Manager of the Biological Psychiatry Laboratory and one my most valued co-workers. Amit Lotan, a psychiatrist, is a fountain of ideas and the highly productive Head of the Translational Neuroscience Group in the laboratory. He is my successor as Director of the Laboratory.

 

Thyroid and depression: Old ideas and new directions

 

        Since the beginning of my career in psychiatry I have been interested in the interaction between thyroid hormones and depression. There is an increased incidence of thyroid dysfunction in depression and an increased incidence of depression in hypothyroidism. Thyroid hormone supplementation with triiodothyronine (T3) has long been known to enhance antidepressant effects. In a series of experiments with Michael Newman and Eitan Gur we used in vivo microdialysis to show a possible mechanism. Thyroid hormone significantly increased serotonin levels in rat brain, augmenting the action of antidepressants (Gur, Lifschytz, Lerer and Newman 2002). We demonstrated that the mechanism of this effect was via pre-synaptically located 5-HT1A and 5-HT1B autoreceptors and post-synaptic 5-HT1A receptors (Gur, Lifschytz, Van de Kar et al. 2004). In work with Tzuri Lifschytz we definitively demonstrated that the T3 has dose-dependent antidepressant effects in mouse screening models (Lifschytz, Zozulinsky, Eitan et al. 2011). In a double-blind, randomized controlled trial conducted with Rena Cooper-Kazaz, we showed that T3 clearly potentiates antidepressant effects in depressed patients when administered with sertraline (Cooper-Kazaz, Apter, Cohen et al. 2007). However, it is not possible to administer thyroid hormone to patients for extended periods. We needed a new direction.

        We tried different approaches that were not successful and then decided to develop deiodinase 3 (DIO3) inhibitors. Why DIO3 inhibitors? Because DIO3 breaks down the thyroid hormone, T3, specifically in brain. The idea was that this could be a route to increase T3 levels in brain but not in tissues where we do not want to increase the hormone. Working with Prof. Govindisamy Mugesh at the Indian Institute of Sciences in Bangalore, we synthesized a series of putative DIO3 inhibitors (European and US patients for which were granted in 2019) and have been testing them in the laboratory for antidepressant effects. We have initial evidence for antidepressant effects and are investing more effort to take this further.

        An exciting development has been a potential role for our DIO3 inhibitors in cancer. Reading about DIO3, I realized that this enzyme is greatly activated in several common cancers. One of these is ovarian cancer. DIO3 activation in cancer may be understood on the background of the fact that thyroid hormone promotes differentiation of cells which is exactly the opposite direction that cancer cells go. Thus, DIO3 is activated in certain cancers in order to break T3 down and impair differentiation. Working with Dr. Osnat Ashur-Fabian, of Meir Hospital in Kfar Saba, we have evidence that our DIO3 inhibitors do indeed inhibit the growth of ovarian cancer cells in culture, particularly high-grade cancer cells. Further experiments are in progress.

 

Genetics and pharmacogenetics: From association to function

 

        I became interested in genetics while still at Ezrath Nashim in the 1980s because of my search for tools that could help to understand the biology of major psychiatric disorders. As the spectacular new tools of molecular medicine became available, I decided to use them in this search.  I was fortunate to be invited to join several European collaborative groups that were setting up genetic programs in schizophrenia and also to collaborate with Miron Baron of Columbia University on genetic studies of bipolar disorder. In this work we recruited large cohorts of carefully characterized patients and families that have been the basis for a wealth of studies.

 

        One of our most striking efforts has been the work we have done with a schizophrenia family sample that we recruited at Taibe Mental Health Center in Israel in collaboration with Dr. Adnan Hamdan. This sample has unique characteristics that make it ideal for genetic studies. Working with Fabio Macciardi in Milan and Doron Lancet and his group at Israel’s Weizmann Institute, we set out on a search for schizophrenia genes. Years of effort led us first to a demonstration of linkage to schizophrenia on chromosome 6q in 2003 (Lerer, Segman, Hamdan et al. 2003) and then, in 2007, to association with schizophrenia of the Abelson Helper Integration Site 1 (AHI1) gene located in the chromosome 6q23 region (Amann-Zalcenstein, Avidan,  Kanyas et al. 2007). This association has been replicated by several other groups including in a large European sample (Ingason, Giegling, Cichon et al. 2010). Ahi1 is not associated with schizophrenia in all samples but it has a role in schizophrenia that needs to be understood.

        Ahi1 is a very important gene in neurodevelopment and is a key component of the primary cilium, a cellular organelle with a key role in chemical sensation, signal transduction, and control of cell growth. Loss of function mutations in AHI1 cause the serious neurological disorder, Joubert Syndrome. We hypothesized that genetic association of Ahi1 with schizophrenia is more likely to be due to variants that influence gene expression. For several years we have been studying the neurobiological role of Ahi1 in mice that are genetically modified to have reduced expression of the gene (heterozygous for a knockout mutation). We have shown that Ahi1 (Jouberin) protein levels are significantly lower in the newborn brains of our genetically modified mice than in wild type mice (Lotan, Lifschytz, Slonimsky et al. 2013). A striking characteristic of these mice is that they manifest reduced levels of anxiety when exposed to anxiety-provoking situations such as the elevated plus maze (Lotan, Lifschytz, Slonimsky et al. 2013; Lotan, Lifschytz, Mernick et al. 2017). We have interpreted this observation as reflecting impaired perception of potential danger. Our heterozygous Ahi1 knockout mice also have a reduced response to the effects of chronic unpredictable stress as shown by the sucrose preference test (Wolf, Lifschytz, Ben-Ari et al. 2018). These characteristics may be related to impaired connectivity of key brain regions such as the amygdala, which we have seen on functional MRI (Lotan, Lifschytz, Slonimsky et al. 2013; Lotan, Lifschytz, Mernick et al. 2017). Understanding how Ahi1 contributes to schizophrenia susceptibility is a challenge we continue to address in the laboratory.

        In parallel with my interest in the genetic causation of psychiatric disorders, I have worked for the past 20 years on the role genetic factors in response to psychotropic drugs and adverse effects. The field of pharmacogenetics has evolved into personalized or precision medicine and has become a major focus of research. My book on Pharmacogenetics of Psychotropic Drugs was published by Cambridge University Press in 2002 (Lerer 2002) and was one of the first. In a series of studies with Ronen Segman and Lior Greenbaum, we invested considerable effort to identify genetic factors that predispose to tardive dyskinesia and antipsychotic-induced parkinsonism, serious adverse effects of antipsychotic drugs (Lerer, Segman, Fangerau et al. 2002; Lerer, Segman, Tan et al. 2005; Greenbaum, Strous, Kanyas et al. 2007). Another key focus in pharmacogenetics has been on genetic factors that influence nicotine addiction in young women. Starting with our first paper in 2006 (Greenbaum, Kanyas, Karni et al. 2006), we have published seven papers on this topic addressing the question, “Why Do Young Women Smoke?” Although we found several genetic variants that are associated, the question still remains an open one, from the genetic as well as other perspectives,

 

Focus on the environment: Challenge for the future

 

        One of Freud’s articles that greatly influenced me was “Mourning and Melancholia,” first published in 1917 (Freud 1917). It deals with the role of loss in depression from a psychoanalytic perspective. I had always wanted to test Freud’s hypothesis associating depression and loss in an empirical study. I designed and implemented such a study with Ofer Agid. It was published in 1999 in Molecular Psychiatry (Agid, Shapira, Zislin et al. 1999). We showed that early parental loss does indeed predispose to depression and other psychiatric disorders. But there is an important point to note. It is not loss due to death that has an effect but loss due to separation – abandonment, divorce and other similar events. Our highly cited findings were confirmed in a collaborative study with Laura Canetti and colleagues (Canetti, Bachar, Bonne et al. 2000).

        I end with Freud and the environment because I believe that gene-environment interaction is going to be a key factor in understanding the biological basis of psychiatric disorders. A direct gene-phenotype link has proved elusive in spite of huge investments and enormous sample sizes. Rare variants may yet be found but it seems almost certain that common variants of major effect will not. How environmental factors alter gene expression and thereby underlie the pathogenesis of major psychiatric disorders is one of the foremost challenges we need to address. Epigenetic effects are certainly involved and non-coding RNAs too. In my opinion gene-environment interaction is the brave new frontier of biological psychiatry.

 

The International Journal of Neuropsychopharmacology

 

        In concluding, I would like to mention the International Journal of Neuropsychopharmacology which was a major focus of my attention for a full decade (Lerer, Frazer, Stahl et al. 1998; Lerer 2008). I founded the journal at the request of the International College of Neuropsychopharmacology (CINP) in 1998 and was Editor in Chief for 10 years. I was fortunate to have chosen excellent Field Editors from all over the world and to have to Irena Luna as the Journal Administrator.  In 10 years the impact factor of the journal rose from zero to 4.7 and it became one of the more influential publications in psychopharmacology. In 2008 I decided to step down from the position of Editor in Chief and was succeeded by Alan Frazer.

 

Mentorship

 

        What is the most precious image I take with me after 40 years in psychiatry? It is a picture taken with a group of mentees who were at the Israel Society for Biological Psychiatry Conference in 2012 when I received the Distinguished Mentor Award. It was an incomparable moment for me. Many thanked me then and thereafter for what I have given them. Their thanks are deeply appreciated but I have received far more than I have given. More than enriching others, I have been enriched!

 

Conclusions

 

        There are a few messages that I hope this Perspective will send to those entrusted with next 40 years of psychiatry:

· I hope that younger people will take home the message that there are few things in the world as interesting as biological psychiatry. Research in this field is immensely challenging but hugely rewarding.

· I hope that department and hospital heads will take home the message that clinical and academic excellence are two sides of the same coin. Without sufficient time to do research there cannot be academic excellence.

· The intellectual rewards of doing research are enormous and worth every effort invested. But that is not all. In the course of a research career one meets fascinating people and builds international friendships that last a lifetime.

 

Acknowledgements

 

        To my wife, Ziona, for her unwavering support of my scientific career; to the Hadassah Biological Psychiatry Laboratory team with whom I work on a daily basis; to my many mentees, co-workers and collaborators who share my research achievements; to the funding agencies that have supported our research; and to Yoav Kohn, my mentee and collaborator, who organized and chaired the International Conference on New Horizons in Biological Psychiatry, Jerusalem, June 2018, at which this lecture was presented.

 

References:

Agid O, Shapira B, Zislin J, Ritsner M, Hanin B, Murad H, Troudart T, Bloch M, Heresco-Levy U, Lerer B. Environment and vulnerability to major psychiatric illness: A case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Molecular Psychiatry. 1999; 4:163-72. 

Amann-Zalcenstein D, Avidan N,  Kanyas K, Ebstein, RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O, Mujaheed M, Segman R.H, Maier W, Macciardi F,  Beckmann J.S, Lancet D, Lerer B. AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. European Journal of Human Genetics. 2006; 14:1111-19.  

Canetti L, Bachar E, Bonne O, Agid O, Lerer B, Kaplan De-Nour A, Shalev AY.  The impact of parental death versus separation from parents on the mental health of Israeli adolescents. Comprehensive Psychiatry.  2000; 41:360-8. 

Cooper-Kazaz R, Apter JT, Cohen R, Karagichev L, Muhammed-Moussa S, Grouper D,  Drori T, Newman ME, Sackeim HA, Glaser B, Lerer B. A randomized, double masked, placebo-controlled trial of combined treatment with sertraline and triiodothyronine in major depression. Arch Gen Psychiatry. 2007; 64(6):679-88.  

Freud S. Mourning and Melancholia. The Standard Edition of the Complete Psychological Works of Sigmund Freud, Volume XIV (1914-1916): On the History of the Psycho-Analytic Movement, Papers on Metapsychology and Other Works, 1917, pp. 237-58 

Greenbaum L, Kanyas K, Karni O, Merbl Y, Olender T, Horowitz A, Yaki, A, Lancet D, Ben-Asher E, Lerer B. Why do young women smoke? Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes. Molecular Psychiatry. 2006; 11:312-22.  

Greenbaum L, Strous RD, Kanyas K, Merbl Y, Horowitz A, Karni O, Katz E, Kotler M, Olender T, Deshpande SN, Lancet D, Ben-Asher E, Lerer B. Association of the RGS2 gene with extrapyramidal symptoms (EPS) induced by treatment with antipsychotic medication. Pharmacogenetics and Genomics 2007; 17:519-28. 

Gur E, Lifschytz T, Lerer B, Newman ME.  Effects of triiodothyronine and imipramine on basal 5-HT levels and 5-HT1 autoreceptor activity in rat cortex. European Journal of Pharmacology 2002; 457:37-43. 

Gur E, Lifschytz T, Van de Kar LD, Lerer B, Newman ME. Effects of triiodothyronine on 5-HT1A and 5-HT1B autoreceptor activity, and postsynaptic 5-HT1A receptor activity in rat hypothalamus. Psychoneuroendocrinology. 2004; 29:1172-83. 

Ingason A, Giegling I, Cichon S, Hansen T, Rasmussen HB, Nielsen J, Jürgens G, Muglia P, Hartmann AM, Strengman E, Vasilescu C, Mühleisen TW, Djurovic S, Melle I, Lerer B, Möller HJ, Francks C, Pietiläinen OP, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Walshe M, Vassos E, Di Forti M, Murray R, Bonetto C, Tosato S; GROUP Investigators, Cantor RM, Rietschel M, Craddock N, Owen MJ, Peltonen L, Andreassen OA, Nöthen MM, St Clair D, Ophoff RA, O'Donovan MC, Collier DA, Werge T, Rujescu D. A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia. Hum Mol Genet. 2010;19(7):1379-86.

Lerer B. Odyssey into the unknown: a resident's views on psychotherapy and supervision. Israel Annals of Psychiatry and Related Disciplines. 1979; 17:74-80.  

Lerer B, Belmaker RH.  Receptors and the mechanism of action of ECT. Biological Psychiatry. 1982; 17:497-511. 

Lerer B, Ebstein RP, Belmaker RH.  Subsensitivity of beta-adrenergic adenylate cyclase after salbutamol treatment in depression. Psychopharmacology 1981; 75:169-72. 

Lerer, B.  Studies on the role of brain cholinergic systems in the therapeutic mechanisms and adverse effects of ECT and lithium (Winning Paper, A.E. Bennet Award, Basic Science, 1984). Biological Psychiatry. 1985; 20:20-40. 

Lerer B, Weiner RD, Belmaker RH, editors.  ECT: Basic Mechanisms. John Libbey, London, 1984. (Republished by American Psychiatric Press, Washington, D.C, 1986). 

Lerer B, Moore N, Meyendorff E, Cho S-R, Gershon, S.  Carbamazepine versus lithium in mania: A double blind study. Journal of Clinical Psychiatry. 1987; 48:89-93. 

Lerer B, Shapira B, Calev A, Tubi N, Drexler H, Kindler S, Lidsky D, Schwartz, JE.  Antidepressant and cognitive effects of twice versus three times weekly ECT. American Journal of Psychiatry 1995; 152:564-70.  

Lerer B, Frazer A, Stahl SM, Farde L, Lesch KP. The International Journal of Neuropsychopharmacology. Int J Neuropsychopharmacol. 1998; 1:1-2.  

Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge University Press, Cambridge, 2002. 

Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R, Aschauer HN, McCreadie RG, Ohlraun S, Ferrier N, Masellis M, Verga M, Scharfetter J, Rietschel  M, Lovlie R, Heresco Levy U, Kennedy JL, Steen VM, Macciardi F. Pharmacogenetics of tardive dyskinesia: Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9gly polymorphism. Neuropsychopharmacology. 2002; 27:109-19. 

Lerer B, Segman RH, Hamdan A,  Kanyas K, Karni O, Kohn Y, Korner M, Lanktree M, Kaadan M, Turetsky N, Yakir A, Kerem B, Macciardi F. Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Molecular Psychiatry. 2003; 8:488-98. 

Lerer B, Segman RH, Tan E-C, Basile VS, Cavallaro R, Aschauer HN, Strous R,  Chong S-A, Heresco-Levy U, Verga M, Scharfetter J, Meltzer HY, Kennedy JL, Macciardi F.  Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype.  Int J Neuropsychopharmacol. 2005; 8:411-25. 

Lerer B. IJNP: A decade in perspective. Int J Neuropsychopharmacol. 2008; 11(8):1035-6. (Editorial). 

Lifschytz T, Zozulinsky P, Eitan R, Landshut G, Ohayon S, Lerer B.  Effect of triiodothyronine on antidepressant screening tests in mice and on presynaptic 5-HT1A receptors: Mediation by thyroid hormone alpha receptors. Journal of Pharmacology and Experimental Therapeutics. 2011; 337:494-502.  

Lotan A, Lifschytz T, Mernick B, Lory O, Levi E, Ben-Shimol E, Goelman G, Lerer B.  Alterations in expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: Translational evidence from the stress-resilient Ahi1 knockout mouse. Molecular Psychiatry. 2017; 22:884-99.  

Lotan A, Lifschytz T, Slonimsky A, Broner EC, Greenbaum L, Abedat S, Fellig Y, Cohen H, Lory O, Goelman G, Lerer B. Neural mechanisms underlying stress resilience in Ahi1 knockout mice: Relevance to neuropsychiatric disorders. Molecular Psychiatry. 2014; 19:243-52.  

Newman M, Lerer B.  Post-receptor mediated increases in adenylate cyclase activity after chronic antidepressant treatment: Relationship to receptor desensitisation. European Journal of Pharmacology 1989a; 162:345-52. 

Newman M, Lerer B.  Effects of chronic electroconvulsive  shock on D1 and D2 dopamine receptor-mediated adenylate cyclase activity in rat striatal and limbic forebrain homogenates. Neuropharmacology 1989b; 28:787-90. 

Shapira B, Lerer B, Gilboa D, Drexler H, Kugelmass S, Calev A. Facilitation of electroconvulsive therapy by caffeine pretreatment. American Journal of Psychiatry 1987; 144:1199-1202. 

Shapira B, Lerer B, Kindler S, Lichtenberg P, Gropp C, Ebstein B, Cooper TB, Calev A.  Enhanced serotonergic responsivity following electroconvulsive therapy in patients with major depression. British Journal of Psychiatry 1992; 160:223-29.  

Shapira B, Tubi N, Drexler, H, Lidsky D, Calev A, Lerer B.  Cost and benefit in the choice of ECT schedule: A new controlled trial of twice versus three times weekly ECT. British Journal of Psychiatry 1998; 172:44-8. 

Vetulani J, Sulser F. Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature. 1975; 257(5526):495-6. 

Wolf G, Lifschytz T, Ben-Ari H, Tatarsky P, Kreisel Merzel T, Lotan A, Lerer B. Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: Behavioral manifestations and neurobiological correlates. Translational Psychiatry. 2018; 8(1):124.

  

*This Perspective is based on a lecture that was delivered at the International Conference on New Horizons in Biological Psychiatry, held in honor of the 70th birthday of Bernard Lerer; Mishkenot Shaananim Conference Center, Jerusalem, June 21, 2018. A version of the Perspective was published in the Israel Journal of Psychiatry, 2018; 55:65-71, and can be viewed at  https://www.youtube.com/watch?v=Fge_dQ_I80A.

 

September 24, 2020