onsdag, 01-12-2021

Thomas A.Ban, editor. Lithium in Psychiatry in Historical Perspective.

 

Bruno Müller-Oerlinghausen’s comment

A professional life dedicated to lithium

 

 

Introduction

        About 20 years ago, I was asked by my esteemed colleagues Thomas Ban, David Healy and Edward Shorter to contribute an autobiographical sketch for an upcoming book edited by CINP: The triumph of psychopharmacology. I titled this short chapter “Destination and serendipity in the career of a clinical psychopharmacologist.”

        It was not written on my cradle that I would become a lithium researcher, but during my childhood I developed a strong interest in chemistry and conducted all kinds of experiments. A special blessing must have protected my family, for our house did not lose its roof; burned hair or eyebrows, however, were some unavoidable “side effects.” I studied chemistry when I entered university, but after a short time, I found it boring. I switched to psychology because I had also developed a keen interest in psychological problems and theories, possibly the result of psychiatric illness in some family members, but this did not satisfy me, either: I missed scientific attractiveness. At length, I ended up studying medicine, but I also tried to acquire a basic understanding of philosophical questions and concepts.

        After passing my state examination, I started postgraduate training in pharmacology. In 1969, the German government sent me to Bangkok to train Thai pharmacologists in the scientific investigation of Thai traditional herbal medicine. After two years, I returned to Germany but not to my former Institute; instead, I joined the Psychiatric Department of the Freie Universität Berlin. On the advice of professor Hanns Hippius, I did not restrict my activities to laboratory work but underwent training in clinical psychiatry. I clearly remember what he said to me on his last day in our department before he moved to Munich University:

        “May I give you some personal advice? If you intend to gain influence on the pharmacological treatment strategies in the department – and I know this is in your mind – then you should first of all gain clinical competence; otherwise, nobody will listen to you.”

        So, I did, and I’m very grateful for the excellent clinical guidance I received from professor Hanfried Helmchen, who had been elected to succeed professor Hippius. My clinical training turned out to be very important for my later professional life, both as an academic lecturer in clinical pharmacology and pharmacotherapy and as chairman of the very influential and traditional Drug Commission of the German Medical Association, a position I held for 12 years.

        In 1972, I was appointed head of the Berlin Lithium Clinic (BLC), which professor Hippius founded in 1967. While there, I saw, advised and treated hundreds of bipolar and other outpatients until I was discharged from my academic duties in 2001. My theoretical reflections, sought-after advice, scientific papers, public proposals and political activities are the fruit of my 29 years at the BLC because they were all based on, and corrected by, the long-lasting personal experiences I had with my patients.

        During my training at the Pharmacological Institute of the University of Göttingen, I never heard a word about lithium. After my first contact with lithium-treated patients, however, I was immediately fascinated. How could a simple ion exert such powerful psychiatric effects without producing mental side-effects, such as I had seen associated with the use of antidepressants and neuroleptic compounds? I spoke with many of my patients for hours to learn about the subjective and objective changes in their experience and behavior. It was the beginning of a very fruitful cooperation with experimental psychologists, neurophysiologists and psychotherapists, but this will become a special topic to be discussed below.

        We published about 250 lithium-related scientific papers in journals or as contributions to handbooks or other publications. In addition, many of my long-term co-workers added their own original contributions to the BLC publication list. Authors of recent publications often refer to the systematic and objective way the BLC collected patient data during its existence. Unfortunately, after 34 years the BLC was abruptly and unexpectedly closed in 2001 by the department’s newly appointed director.  The extremely valuable long-term patient data, however, were saved by a “secret mission” by Anne Berghöfer, and they still serve as basic material for studies by other authors, e.g., on the predictability of lithium response (Nunes, Ardau, Berghöfer et al. 2020). In 2017 we celebrated 50 years of continuous research and patient care at the lithium clinics of Dresden and Berlin (Felber, Bauer, Lewitzka and Müller-Oerlinghausen, 2018).

        Specialized patient care and high-level research activities, however, continued under the academic and clinical activities of Tom Bschor, former director of Dept. of Psychiatry at Schlosspark-Klinik Berlin, and Michael Bauer, present Chairman of the Psychiatric Department at the University of Dresden, together with Werner Felber and Ute Lewitzka, the longstanding secretary of the International Group for the Study of Lithium-Treated Patients (IGSLI) and well-known specialist in suicidology.

        For the sake of readability and brevity, in the following sections, I will not offer a comprehensive list of our lithium-related articles because these can be easily searched on my personal website (www.bruno-mueller-oerlinghausen.de); instead, I will quote only selected references that I dare consider to be important scientific contributions to various aspects of lithium and its medical use.

        In 1986, together with Waldemar Greil, former head of the Lithium Clinic in the Department of Psychiatry at the University of Munich, we edited the first German edition of our compendium, Lithium Therapy: Benefits, Risks and Alternatives. A second edition appeared in 1997 with Anne Berghöfer as the third editor (Müller-Oerlinghausen, Greil and Berghöfer 1997). This became an important reference book on lithium for German, Swiss and Austrian psychiatrists, and many of its chapters are based on the practical experiences and scientific findings obtained during day-to-day work at the BLC.

        In 2000, together with Michael Bauer and my colleague and close friend Paul Grof, with whom I share many lithium-related thoughts and experiences, we edited the first comprehensive guide in English, Lithium in Neuropsychiatry, also on behalf of IGSLI. Dedicated to professor Mogens Schou, it covers nearly every important aspect of lithium treatment. A total of 84 international experts contributed to this impressive volume (Bauer, Grof and Müller-Oerlinghausen 2006). The most recent short guide for prescribers and users of lithium salts, based on much discussion and collaboration within the IGSLI group of lithium researchers, was conceptualized and presented by Tondo, Alda, Bauer et al. in 2019. In the same year, I presented a comprehensive CME article on lithium for German-speaking psychiatrists (Müller-Oerlinghausen 2019).

        In what follows, I touch upon five points central to our scientific interest that are related to and inspired by our care of long-term lithium-treated patients at the BLC (Felber, Bauer, Lewitzka and Müller-Oerlinghausen 2018).

1) Special value of systematic follow-up studies in selected patient cohorts

        Why should long-term outpatient studies be valued over classical RCTs or major epidemiological studies? The simple answer is that the people conducting the studies know exactly what they mean when they evaluate and discuss the long-term treatment data collected in such a patient population.

        The drawback of most RCTs is that their data stem from highly selected patient samples that are not usually representative of the majority of patients, those that seek our help in “true world settings.” In this respect, the patient cohorts of large epidemiological studies might often be closer to reality; however, the inherent problem with them is that essential contaminating factors such as patient adherence, comorbidities, lifestyle or everyday functionality are often not disclosed. Consequently, one of my first regular activities at the BLC was to develop accurate, standardized and comprehensive patient documentation. This was one of the essentials that enabled us, for example, to use the ALDA scale of lithium response. Developed by Martin Alda (Halifax), it became an important research tool for answering important real-life questions such as, “Which are the characteristics of excellent lithium responders?”

        Based on precisely documented records of every patient’s course of treatment, Berghöfer et al. were able to demonstrate that, contrary to the general view, there was no loss of prophylactic efficacy over the long-time course of a well-monitored lithium medication (Berghöfer and Müller-Oerlinghausen 2000). We also proved that discontinuing and restarting a course of lithium medication was not associated with diminished efficacy, at least not in patients with “classical” bipolar disorder (Berghöfer, Alda, Adli et al. 2008).

        One of the essentials for gaining reliable data on the response or nonresponse of our patients is certainty about their compliance.  Standardized lithium blood-levels are important but provide only restricted information. Lithium is nearly completely excreted by the kidney. Thus, we measured the amount of lithium in urine over 24 hours. The ratio of the excreted amount to the prescribed daily dose was a reliable measure for a patient’s average adherence, e.g., a ratio of 0.89 indicates an average compliance of 90%. Nevertheless, an individual response rate might depend on intra-individual fluctuations of lithium kinetics.

        Thus, we routinely measured not only lithium plasma levels under standardized conditions but also the intra-erythrocyte lithium concentration. (There have been some suggestions that the erythrocyte lithium level reflects the lithium concentration in the brain.) The ratio of both concentrations is usually around 0.3. However, we observed a disproportionate increase in the intra-erythrocyte concentration in some patients before or during a depressive relapse or in patients with abnormally marked side effects despite having a “normal” lithium plasma level.

        Together with Athanasio Kukopoulos, we studied these mechanisms intensively in a Sardinian patient who was a nurse in Athanasio’s clinic (Kukopoulos, Minnai and Müller-Oerlinghausen 1985). (By the way, this was the only occasion in my scientific life that a female patient, Maria Rosaria, offered her bed and sleeping room to me – the “German Professor,” as Athanasio always introduced me to his patients – since I had to stay for some days in her house so that I could perform all the necessary assessments.) Furthermore, the intra-individual coefficient of variation of lithium plasma levels was calculated successively for every patient at the BLC. Thus, we could check at a glance whether the current blood level at the time of a patient’s visit to the clinic was within his/her intra-individual 95% confidence interval.

2. Mechanism of action of lithium

     a) Psychological and neurophysiological approaches

        As mentioned above, I was especially interested in the mechanism of action of lithium; therefore, I provide a sketch of two different aspects on two different explanatory levels: a) lithium-induced changes to behavior and experience, i.e., on the level of psychology that might show a connection to the changes within a neurophysiological frame of reference, and b) lithium-induced changes on a biochemical level, particularly on serotonergic mechanisms, which drew our interest as a potential interface to changes on the psychological level such as anti-aggressive and anti-suicidal effects.

        During the 1970s, to gain a better understanding of the subjective experience of our patients, we tried to approach their subjective feelings of psychophysical fatigue by means of psychometric, EEG and electromyographic recordings (Girke, Krebs and Müller-Oerlinghausen 1975; Müller-Oerlinghausen, Bauer, Girke et al. 1977).

        Together with clinical psychologist Detlef Kropf and neurophysiologist Werner Herrmann, who worked with the influential group of professor Dieter Bente, we studied the influence of lithium on vigilance, memory, learning and mood of patients and healthy volunteers (Kropf and Müller-Oerlinghausen 1979; Müller-Oerlinghausen, Hamann, Herrmann and Kropf 1979; Müller-Oerlinghausen and Kropf 1979; Herrmann, Kropf, Fichte and Müller-Oerlinghausen 1980; Bente, Scheuler, Ulrich and Müller-Oerlinghausen 1982).

        In a 1982 article for the BJP, I tried for the first time to integrate these and other experimental findings in an approach that could explain the clinical effects of lithium. We dared to hypothesize a link among the neurophysiological effects, compliance and clinical response (Müller-Oerlinghausen 1982).

        In 1986, together with Detlef Kropf, we published our findings, obtained using a complex experimental methodology, on the influence of lithium on the visual perception of symptom-free lithium patients (Kropf and Müller-Oerlinghausen 1986). Our theoretical model on the mechanism of lithium in psychological terms was quite different from the stimulus-reaction model proposed at that time by the psychologist Neil Johnson (Müller-Oerlinghausen 1987, 1997).

        Somewhat disappointing was the reaction of the international scientific world: it appeared as if nobody except Neil Johnson in the U.K. was interested in this type of data. The clinical “pharmaco” psychologists in Germany at that time appeared to be occupied exclusively with experiments and theories on the effects of tranquilizers in healthy volunteers. They missed the chance to add experiment-based psychological concepts to the popular and simplified biochemical hypotheses on the action of neuroleptics or antidepressants. Often at conferences, someone would ask me if I had an opinion about the “real” effect “behind” these psychological phenomena: Change of serotonergic activity? Sodium/potassium fluxes? Blocked 3beta GSK activity?

        The effect of lithium on smooth-pursuit eye movement became another focus of interest in later years (Flechtner, Mackert, Thies et al. 1992). Thomas Wolf, also a clinical psychologist and long-standing member of our group, completed a thorough investigation into the change of cognitive dysfunction, such as lowered self-esteem, under long-term lithium medication in people with bipolar disorders (Wolf and Müller-Oerlinghausen 2002). He provided sufficient evidence to show that successful episode-preventive medication normalized self-esteem after an episode-free period of at least 47 months.

        On the other hand, the presence of cognitive dysfunctions underlined the positive value of additional cognitive behavior therapy in people with bipolar disorders treated with lithium (Wolf 1997). Would it also be proper to describe the mental/behavioral effects of a long-term lithium medication in psychotherapeutic terms? In fact, one of our psychotherapists, Ulrich Rüger, investigated and described the dynamic process of emotional and behavioral structural changes in some of our patients in purely psychoanalytical terms. Within this concept, he explained why a more-or-less therapy-resistant, severe depressive syndrome developed in a patient despite very successful episode-preventive lithium treatment (Rüger 1976).

        More than 10 years later, together with Stephan Priebe, now in the U.K., we examined   the potential influence of expressed emotions among the key relatives of long-term lithium patients on their clinical response in terms of hospital admissions (Priebe, Wildgrube and Müller-Oerlinghausen 1988, 1989).

        It was also in the 1980s when we embarked on methodically refined neurophysiological investigations into the effects of lithium on healthy volunteers (Herrmann WM, Kropf D, Fichte K, Müller-Oerlinghausen 1980; Bente, Scheuler, Ulrich and Müller-Oerlinghausen 1982; Ulrich, Frick, Stieglitz and Müller-Oerlinghausen 1987; Ulrich, Herrmann, Hegerl and Müller-Oerlinghausen 1990). Our studies together with Gerald Ulrich focused on the effects of lithium on the dynamics of EEG-based vigilance. An enhancement of alpha activity and a decrease in the dynamic variability of alpha anteriorization was the prominent effect that we interpreted as further proof of a general “dynamic restriction,” i.e., reduced variability of the system’s behavior.

     b) Biochemical approaches—the role of serotonin

        Aggression and suicide might be associated, on a biochemical level, to changes in the central serotonergic systems. Since lithium, according to our own observations and systematic research, clearly possesses anti-aggressive (Müller-Oerlinghausen and Lewitzka 2010) and anti-suicidal (see below) effects, we searched for peripheral markers of serotonergic activity that could be used in humans.

        Together with HD Mühlbauer in the 1980s, we started to use the fenfluramine-triggered increase in cortisol blood level as a marker in patients and healthy volunteers and were able to prove that long-term lithium responders showed marked serotonin-agonistic reactions that were in line with experimental animal findings, most of which pointed to a presynaptic mechanism (Müller-Oerlinghausen 1985; Mühlbauer and Müller-Oerlinghausen 1985).

        Furthermore, a doctoral thesis showed that the cortisol (and prolactin) response triggered by fenfluramine differed significantly between patients on lithium vs. carbamazepine medication (Mannel, Müller-Oerlinghausen, Czernik and Sauer 1997). Our hope that the routine use of the fenfluramine test would help predict the lithium response in bipolar patients, however, remained unfulfilled (Müller-Oerlinghausen, Mannel, Czernik and Sauer 1993).

        We worked with different peripheral serotonergic markers but, over the years became somewhat more skeptical about their validity and clinical usefulness (Steckler, Rüggeberg-Schmidt and Müller-Oerlinghausen 1993; Thies-Flechtner, Weigel and Müller-Oerlinghausen 1994; Müller-Oerlinghausen, Roggenbach and Franke 2004; Roggenbach, Müller-Oerlinghausen and Franke 2002; Müller-Oerlinghausen and Roggenbach 2002; Lauterbach, Brunner, Hawellek et al. 2006; Kawohl, Hegerl, Müller-Oerlinghausen and Juckel 2008).

        Residents, doctors and colleagues from the Charité, at that time located on the eastern side of the Berlin Wall, were involved in laboratory studies that demonstrated how laboratory and patient-focused work could complement one another. This fruitful harmony between clinical and laboratory work also existed in the area of neurophysiology. Ulrich Hegerl, former director of the Psychiatric Department of the University of Leipzig, now Distinguished Professor at the Department of Psychiatry, Psychosomatics, and Psychotherapy, Goethe-Universität am Main, and founder and head of the Chairman of the European Alliance against Depression (www.EAAD.net), utilized auditory evoked potentials (AEP) as a marker of central serotonergic activity. He found convincing evidence that the steepness of the slope of ASF (N1/P2 amplitude) was related to central serotonergic neurotransmission and to the type of lithium response (Hegerl and Juckel 1993; Hegerl, Prochno, Ulrich and Müller-Oerlinghausen 1988; Hegerl, Herrmann, Ulrich and Müller-Oerlinghausen 1990; Hegerl, Wulff and Müller-Oerlinghausen 1992).

3. The suicide-preventing - and excess mortality-lowering effect of lithium

        I suppose that our most relevant and internationally best-known scientific contribution was the detection and thorough study of the suicide-preventing effect of lithium resulting in a clear-cut 2–3-fold reduction of the excess mortality in patients with affective disorders. How did we become aware of this association? As so often happens in science, serendipity played a decisive role. We had lost within a rather short interval two or three patients who had colon carcinoma. I felt uneasy; could it be that lithium had carcinogenic side effects? I started to look up the diagnoses of patients who had died while at the BLC, and it struck me that not one of those with continuous lithium medication had died from suicide.

        In her doctoral thesis, Barbara Causemann examined the number of suicidal acts in a risk population, i.e., among patients of the BLC with a history of suicidal attempts before being put on lithium (Causemann and Müller-Oerlinghausen 1988; Müller-Oerlinghausen, Müser-Causemann and Volk 1992). Her findings clearly suggested a suicide-preventing effect of long-term lithium treatment.

        At the time, we were unaware of any other systematic study on this exciting effect although some Czech authors and Barraclough from the U.K. had occasionally pointed to its possibility. Before 1989, due to the political situation, there was only a very limited scientific exchange between the western and the eastern parts of Germany. Thus, we had no knowledge of the surprisingly identical but still unpublished observations of Werner Felber, an expert in suicidology at the Psychiatric Department of the University Dresden. It was good luck, then, that a young fellow named Bernd Ahrens joined my research group because he possessed special expertise in calculating standardized mortality rates from epidemiological data. Thus, we were able to demonstrate that well-monitored long-term lithium medication did lower the otherwise approximately 3-fold increased standardized mortality of patients with affective disorders to the level of the general population. 

        Around the same time, Alec Coppen from Edinburgh also reported markedly decreased standardized mortality in long-term, mostly unipolar, treated patients (For a summary of Alec’s important studies on lithium, see reference Abou-Saleh, Müller-Oerlinghausen and Coppen 2017). When I informed Mogens Schou – we had become good friends after Athanasio Kukopoulus had introduced me to him – about the first data showing the possible anti-suicidal effect, he appeared very interested but at the same time doubtful that our results obtained in a relatively small number of German patients would be of international interest. That was the starting point for founding IGSLI, the International Group for the Study of Lithium treated Patients, by Mogens, Paul Grof and me in 1988.

        Now, with the long-term support of a group of experienced European and Canadian lithium researchers, we could test the reliability and stability of our preliminary findings in much larger groups of patients using a variety of methodical approaches (Müller-Oerlinghausen, Ahrens, Grof et al. 1992; Müller-Oerlinghausen, Wolf, Ahrens et al. 1994; Wolf, Müller-Oerlinghausen, Ahrens et al. 1996; Müller-Oerlinghausen, Wolf, Ahrens et al. 1996).

        The mortality-lowering effect was clearly confirmed, and it became clear that this effect could be shown for all groups of affective disorders and that it referred not only to suicide-related but also to excess cardiovascular mortality (Ahrens, Müller-Oerlinghausen, Schou et al. 1995). Bernd Ahrens found supporting evidence that the suicide-preventive effect might to some degree be independent on the response, i.e., the absence of further episodes (Ahrens and Müller-Oerlinghausen 2001). For more on this issue with reference to many international studies and publications, refer to the “mortality data” heading on the IGSLI website, www.igsli.org.

        The specificity of the anti-suicidal effect was demonstrated again in a dramatic manner. Within the ambitious MAP study (a multi-center RCT that lasted 2.5 years comprising approximately 300 bipolar patients, directed by Waldemar Greil), it shocked us to discover that four suicides and five suicide attempts had occurred in the carbamazepine group while none was documented in the lithium group (Thies-Flechtner, Müller-Oerlinghausen, Seibert et al. 1996; Greil, Ludwig-Mayerhofer, Erazo et al. 1997).

        Against the background of these and further findings and with the support of Karla Lehmann, we embarked on a somewhat courageous calculation to estimate the economic benefit of lithium prophylaxis in Germany. For 1992, we calculated a net gain per year of DM 221 million for the gross national product of Germany. Taking also into account the approximately 210 non-occurring suicides per year among the 41,000 patients receiving lithium in West Germany at that time – a roughly 10-fold undermedication – the country would gain ca. 3,000 years of manhours of work before the age of 65 every year. In other words, effective lithium prophylaxis would result in a saving of more than USD 3,000 per year, per patient (Lehmann, Ahrens and Müller-Oerlinghausen 1997; Berghöfer 2006).

        One of the greatest ethical and methodical challenges was the design and performance of a prospective placebo-controlled study on the anti-suicidal effect in patients recruited after having attempted suicide. With the support of the German government, we set up an impressive protocol but were not able to recruit the required number of patients. Nevertheless, we were able to show a statistically significant effect for prevention of suicide but not suicide attempts (Lauterbach, Felber, Müller-Oerlinghausen et al. 2008).

        In cooperation with the Dresden group, we summarized the state-of-the-art in this fascinating area to which, sad to say, many psychiatrists and other professionals still pay surprisingly little attention, thereby involuntarily and needlessly risking the life of their patients suffering from affective disorder (Müller-Oerlinghausen and Lewitzka 2015; Lewitzka, Severus, Bauer et al. 2015).

4. Lithium and the kidney

        Lithium, as well-known, is a potentially nephrotoxic agent. During the 1980s, many clinicians became worried because some reports, mainly from Danish and Australian nephrologists, suggested potentially irreversible severe kidney damage in lithium-treated patients. Together with a nephrologist, we performed thorough investigations including renal biopsies (Albrecht, Kampf, Müller-Oerlinghausen 1980; Müller-Oerlinghausen, Albrecht and Kampf 1981; Kampf, Müller-Oerlinghausen, Albrecht and Kessel 1983).

        Based on our findings and in accordance with other investigators at that time, we concluded that the risk of permanent kidney damage is very low in well-monitored patients. In the meantime, however, as the number of patients receiving lithium for 30 years or longer has grown, another picture has developed. IGSLI contributed to a balanced and scientifically sound view on this special risk of long-term lithium medication (Tondo, Abramowicz, Alda et al. 2017).

        It should be self-evident that, when we act as advisors to a patient with renal failure under long-term treatment with lithium, our first question has to be, “Is this patient a lithium responder?” There can be no doubt that we should not continue lithium treatment in the face of nonresponse or questionable response, yet it is exactly this question that in so many cases cannot be answered sufficiently because of sloppy or even missing documentation on the course of illness in such a patient before and after starting lithium treatment.

        In the case of a clear responder under doubtless compliance, before we recommend discontinuation of lithium, we must carefully balance the misery of new depressive relapses (one of my patients called it “the hell”) against the (very low) risk of life-long dialysis. This is an act of great responsibility that also requires thorough knowledge of the chances of therapeutic success or failure when the patient would be switched to an alternative medication. Thus, particularly my Canadian colleagues observed that excellent lithium responders will mostly react unfavorably to “alternatives,” such as valproate or carbamazepine.

5. Lithium as augmentation strategy

        The use of lithium as an augmentation strategy in patients apparently resistant to antidepressant medication was thoroughly investigated by Michael Bauer together with Tom Bschor, Christopher Baethge and Mazda Adli, all of whom had been active researchers at the BLC (Bauer, Bschor, Kunz et al. 2000; Bschor, Berghöfer, Ströhle et al. 2002). The NNT (the number needed to treat) for adjunctive lithium in otherwise nonresponding patients is 5 according to a meta-analysis (Bauer, Adli, Ricken et al. 2014). However, even though this important strategy is recommended in most serious guidelines, it seems not to be known or accepted by many psychiatrists. The DEX/CRH test was developed as an interesting tool to predict a positive response for lithium augmentation (Bschor, Canata, Müller-Oerlinghausen and Bauer 2001; Bschor, Baethge, Adli et al. 2003).

Conclusion

        This is the end of a short ride through my professional life with lithium. Despite having seen, over the years, the misery of so many patients treated with the most fanciful cocktails of various old and new compounds and not doing better over months and years, I still try to preserve my hope and faith for the increasing dissemination of existing expertise in rational and effective drug treatment. Our patients do deserve our deepest empathy and intellectual excellency in setting up rational pharmacological approaches

        Sometimes, while waiting for the train at an underground station, somebody would very modestly approach me and whisper: “Aren’t you Professor Müller-Oerlinghausen?”   After seeing me nod, he/she would perhaps say: “Do you remember me? I was a patient in the lithium clinic. You really saved my life. After the clinic was closed, I could never find a psychiatric office with comparable expertise and service.” I still remember the names of most of my long-term patients, and moments such as these are when I feel that my many years of exertion and commitment have not been in vain, and the fact that many of my former coworkers such as Michael Bauer, Tom Bschor, Ulrich Hegerl or Mazda Adli all became internationally known experts for the treatment of bipolar disorder depression contributes to my hope and satisfaction.

 

References:

Abou-Saleh MT, Müller-Oerlinghausen B, Coppen AJ. Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression. International Journal of Bipolar Disorders 2017;5(1):11.  

Ahrens B, Müller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001;34(4):132–6.  

Ahrens B, Müller-Oerlinghausen B, Schou M, Wolf T, Alda M, Grof E, Grof P, Lenz G, Simhandl C, Thau KExcess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis. Journal of Affective Disorders 1995;33(2):67–75.  

Albrecht J, Kampf D, Müller-Oerlinghausen B. Renal function and biopsy in patients on lithium-therapy. Pharmakopsychiatrie, Neuro-Psychopharmakologie 1980;13(4):228–34.  

Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. The American Journal of Psychiatry 2000;157(9):1429–35.  

Bauer M, Grof P, Müller-Oerlinghausen B. Lithium in Neuropsychiatry. The Comprehensive Guide. Informa Health Care. Oxon (UK), New York (USA); 2006.

Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs 2014;28:331-42. 

Bente D, Scheuler W, Ulrich G, Müller-Oerlinghausen B. Effects of lithium on the EEG of healthy subjects and psychiatric patients: methods, results and hypotheses. In: Herrmann WM, editor. EEG in Drug research. Gustav Fischer; 1982, pp. 369, m-385. 

Berghöfer A. Economics of lithium prophylaxis in bipolar disorders. In: Bauer M, Grof P, Müller-Oerlinghausen B. Lithium in Neuropsychiatry. The Comprehensive Guide. Informa Health Care. Oxon (UK), New York (USA); 2006, pp. 505-11.  

Berghöfer A, Müller-Oerlinghausen B. Is there a loss of efficacy of lithium in patients treated for over 20 years? Neuropsychobiology 2000;42 Suppl 1:46-9.  

Berghöfer A, Alda M, Adli M, Baethge C, Bauer M, Bschor T, Glenn T, Grof P, Müller-Oerlinghausen B, Rybakowski J, Suwalska A, Pfennig A. Long-term effectiveness of lithium in bipolar disorder: A multicenter investigation of patients with typical and atypical features. J Clin Psychiatry 2008;69(12):1860-8. 

Bschor T, Baethge C, Adli M, Eichmann U, Ising M, Uhr M, Modell S, Künzel H, Müller-Oerlinghausen B, Bauer M. Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. Journal of Psychiatric Research 2003;37(2):135–43.  

Bschor T, Berghöfer A, Ströhle A, Kunz D, Adli M, Müller-Oerlinghausen B, Bauer M. How long should the lithium augmentation strategy be maintained? A 1-year follow-up of a placebo-controlled study in unipolar refractory major depression. Journal of Clinical Psychopharmacology 2002;22(4):427–30.  

Bschor T, Canata B, Müller-Oerlinghausen B, Bauer M. Predictors of response to lithium augmentation in tricyclic antidepressant-resistant depression. Journal of Affective Disorders 2001;64(2-3):261–5. 

Causemann B, Müller-Oerlinghausen B. Does lithium prevent suicides and suicidal attempts? In: Birch NJ, editor. Lithium: Inorganic pharmacology and psychiatric use. IRL Press, Oxford; 1988, pp.23-4. 

Felber W, Bauer M, Lewitzka U, Müller-Oerlinghausen B. Lithium Clinics in Berlin and Dresden: a 50-Year Experience. Pharmacopsychiatry 2018;51(5):166-171.  

Flechtner KM, Mackert A, Thies K, Frick K, Müller-Oerlinghausen B. Lithium effect on smooth pursuit eye movements of healthy volunteers. Biological Psychiatry 1992;32(10):932-8.  

Girke W, Krebs FA, Müller-Oerlinghausen B. Effects of lithium on electromyographic recordings in man. Studies in manic-depressive patients and normal volunteers. Int Pharmacopsychiatry 1975;10(1):24-36.  

Greil W, Ludwig-Mayerhofer W, Erazo N, Schöchlin C, Schmidt S, Engel RR, Czernik A, Giedke H, Müller-Oerlinghausen B, Osterheider M, Rudolf GA, Sauer H, Tegeler J, Wetterling T. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders--a randomised study. Journal of Affective Disorders 1997;43(2):151–61.  

Hegerl U, Juckel G. Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: A new hypothesis. Biol Psychiatry 1993;33(3):173-87. 

Hegerl U, Herrmann WM, Ulrich G, Müller-Oerlinghausen B. Effects of lithium on auditory evoked potentials in healthy subjects. Biological Psychiatry 1990;27(5):555–60.

Hegerl U, Prochno I, Ulrich G, Müller-Oerlinghausen B. Are auditory evoked potentials suitable for predicting the response to lithium prophylaxis? A study on the effects of repeated measurement, age, gender, and personality on the amplitude/stimulus intensity function in healthy volunteers. Pharmacopsychiatry 1988;21(6):336–7.

Hegerl U, Wulff H, Müller-Oerlinghausen B. Intensity dependence of auditory evoked potentials and clinical response to prophylactic lithium medication: A replication study. Psychiatry Research 1992;44(3):181–90.

Herrmann WM, Kropf D, Fichte K, Müller-Oerlinghausen B. Elektroenzephalographische und psychoexperimentelle Untersuchungen mit Lithium an gesunden Probanden [Electroencephalographic and psychoexperimental studies in healthy subjects on lithium medication (author's transl)]. Pharmakopsychiatrie, Neuro-Psychopharmakologie 1980;13(4), 200–12.

Kampf D, Müller-Oerlinghausen B, Albrecht J, Kessel M. Lithium-Prophylaxe: Nephrotoxizität und therapeutische Konsequenzen [Lithium prophylaxis: nephrotoxicity and therapeutic consequences]. Der Internist 1983;24(2):110–16. 

Kawohl W, Hegerl U, Müller-Oerlinghausen B, Juckel G. Einblicke in die zentrale serotonerge Funktion bei Patienten mit affektiven Störungen [Insights in the central serotonergic function in patients with affective disorders]. Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Österreichischer Nervenarzte und Psychiater 2008;22(1):23–7. 

Kropf D, Müller-Oerlinghausen B. Changes in learning, memory, and mood during lithium treatment. Approach to a research strategy. Acta Psychiatr Scand 1979;59(1):97-124. 

Kropf D, Müller-Oerlinghausen B. Effects of lithium on visual perception in manic-depressive patients without acute symptomatology. Neuropsychobiology 1986;15(1):34–42. 

Kukopoulos A, Minnai G, Müller-Oerlinghausen B. The influence of mania and depression on the pharmacokinetics of lithium. A longitudinal single-case study. J Affect Disord 1985;8(2):159-66. 

Lauterbach E, Brunner J, Hawellek B, Lewitzka U, Ising M, Bondy B, Rao ML, Frahnert C, Rujescu D, Müller-Oerlinghausen B, Schley J, Heuser I, Maier W, Hohagen F, Felber W, Bronisch T. Platelet 5-HT2A receptor binding and tryptophan availability in depression are not associated with recent history of suicide attempts but with personality traits characteristic for suicidal behavior. Journal of Affective Disorders 2006;91(1):57–62.  

Lauterbach E, Felber W, Müller-Oerlinghausen B, Ahrens B, Bronisch T, Meyer T, Kilb B, Lewitzka U, Hawellek B, Quante A, Richter K, Broocks A, Hohagen F. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: A randomised, placebo-controlled, 1-year trial. Acta Psychiatrica Scandinavica 2008;118(6):469–79.  

Lehmann K, Ahrens B, Müller-Oerlinghausen B. Pharmaökonomie der Lithiumprophylaxe. In: Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Nutzen, Risiken, Alternativen, 2nd ed. Springer, Berlin-Heidelberg-New York; 1997, pp. 459-65. 

Lewitzka U, Severus E, Bauer R, Ritter P, Müller-Oerlinghausen B, Bauer M. The suicide prevention effect of lithium: More than 20 years of evidence-a narrative review. International Journal of Bipolar Disorders 2015;3(1):32.  

Mannel M, Müller-Oerlinghausen B, Czernik A, Sauer H. 5-HT brain function in affective disorder: D,l-fenfluramine-induced hormone release and clinical outcome in long-term lithium/carbamazepine prophylaxis. Journal of Affective Disorders 1997;46(2):101–13.  

Mühlbauer HD, Müller-Oerlinghausen B. Fenfluramine stimulation of serum cortisol in patients with major affective disorders and healthy controls: Further evidence for a central serotonergic action of lithium in man. Journal of Neural Transmission 1985;61(1-2):81–94.  

Müller-Oerlinghausen, B. Psychological effects, compliance, and response to long-term lithium. The British Journal of Psychiatry: The Journal of Mental Science 1982;141:411–19. 

Müller-Oerlinghausen B. Lithium long-term treatment--does it act via serotonin? Pharmacopsychiatry 1985;18(2):214–17.  

Müller-Oerlinghausen B. Mental functioning. In: Johnson FN, editor. Depression, Mania. Modern Lithium Therapy. IRL Press Ltd. Oxford, Washington; 1987, pp 246-52. 

Müller-Oerlinghausen B. Erklärungsebenen der Wirkungen von Lithium auf menschliches Erleben und Verhalten. In: Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Nutzen, Risiken, Alternativen, 2nd ed. Springer, Berlin-Heidelberg-New York; 1997, pp. 19–21. 

Müller-Oerlinghausen B. Lithium heute – ein Update seiner Wirksamkeit und Risiken. NeuroTransmitter 2019;30(10):46-55. 

Müller-Oerlinghausen B, Ahrens B, Grof E, Grof P, Lenz G, Schou M, Simhandl C, Thau K, Volk J, Wolf R. The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness. Acta Psychiatrica Scandinavica 1992;86(3):218–22.  

Müller-Oerlinghausen B, Albrecht J, Kampf D. Lithium-Prophylaxe und Nierenfunktion. Zusammenfassende Beurteilung und Richtlinien zur Therapieüberwachung [Lithium prophylaxis and renal function. Conclusions and guidelines for treatment control (author's transl)]. Der Nervenarzt 1981;52(2):113–15. 

Müller-Oerlinghausen B, Bauer H, Girke W, Kanowski S, Goncalves, N. Impairment of vigilance and performance under lithium-treatment. Studies in patients and normal volunteers. Pharmakopsychiatr Neuropsychopharmakol 1977;10(2):67-78. 

Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Nutzen, Risiken, Alternativen, 2nd ed. Springer, Berlin-Heidelberg-New York; 1997. 

Müller-Oerlinghausen B, Hamann S, Herrmann WM, Kropf D. Effects of lithium on vigilance, psychomotoric performance and mood. Pharmakopsychiatr Neuropsychopharmakol 1979;12(5):388-96. 

Müller-Oerlinghausen B, Kropf D. Effects of lithium on normal experience and behaviour. Conditional and descriptive approach to the structure of its action. In: Strömgren E, Schou M, editors. Origin, prevention and treatment of affective disorders. Academic Press, N.Y.; 1979, pp. 42–63. 

Müller-Oerlinghausen B, Lewitzka U. Lithium reduces pathological aggression and suicidality: A mini-review. Neuropsychobiology 2010;62(1):43–49.  

Müller-Oerlinghausen B, Lewitzka U. The contribution of lithium and clozapine for the prophylaxis and treatment of suicidal behavior. In: Kaschka WP, Rujescu D, editors. Biological aspects of suicidal behavior. Karger AG, Basel (Switzerland); 2015, pp. 145–60.  

Müller-Oerlinghausen B, Mannel M, Czernik A, Sauer H. Fenfluramine stimulation of cortisol in patients with affective psychoses: a predictor for response to lithium/carbamazepine prophylaxis? In: Birch NJ, Padgham C, Hughes MS, editors. Lithium in medicine and Biology. Marius Press, Camforth (UK); 1993, pp. 143-50.  

Müller-Oerlinghausen B, Müser-Causemann B, Volk J. Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. Journal of Affective Disorders 1992;25(4):261–9.  

Müller-Oerlinghausen B, Roggenbach J. Concretism in biological suicide research -- are we eating the menu instead of the meal? Some thoughts on present research strategies. Pharmacopsychiatry 2002;35(2):44–9. 

Müller-Oerlinghausen B, Roggenbach J, Franke L. Serotonergic platelet markers of suicidal behavior--do they really exist? Journal of Affective Disorders 2004;79(1-3):13–24.  

Müller-Oerlinghausen B, Wolf T, Ahrens B, Schou M, Grof E, Grof P, Lenz G, Simhandl C, Thau K, Wolf R. Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients. Acta Psychiatrica Scandinavica 1994;90(4):295–7.  

Müller-Oerlinghausen B, Wolf T, Ahrens B, Glaenz T, Schou M, Grof E, Grof P, Lenz G, Simhandl C, Thau K, Vestergaard P, Wolf R. Mortality of patients who dropped out from regular lithium prophylaxis: A collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI). Acta Psychiatrica Scandinavica 1996;94(5):344–7.  

Nunes A, Ardau R, Berghöfer A, Bocchetta A, Chillotti C, Deiana V, Garnham J, Grof E, Hajek T, Manchia M, Müller-Oerlinghausen B, Pinna M, Pisanu C, O'Donovan C, Severino G, Slaney C, Suwalska A, Zvolsky P, Cervantes P, del Zompo M, Grof P, Rybakowski J, Tondo L, Trappenberg T, Alda M. Prediction of lithium response using clinical data. Acta Psychiatr Scand 2020;141(2):131-141. 

Priebe S, Wildgrube C, Müller-Oerlinghausen B. Lithium prophylaxis and expressed emotion. Br J Psychiatry 1989;154:396-9. 

Priebe S, Wildgrube C, Müller-Oerlinghausen B. Expressed emotions and hospital admissions in lithium prophylaxis. In: Birch N, editor. Lithium: Inorganic pharmacology and psychiatric use. IRL press Ltd. Oxford; 1988, pp. 29–31. 

Roggenbach J, Müller-Oerlinghausen B, Franke L. Suicidality, impulsivity and aggression--is there a link to 5HIAA concentration in the cerebrospinal fluid? Psychiatry Research 2002;113(1-2):193–206.  

Rüger U. Tiefenpsychologische Aspekte des Verlaufs phasischer Depressionen unter Lithiumprophylaxe. Nervenarzt 1976;9:538–43.  

Steckler T, Rüggeberg-Schmidt K, Müller-Oerlinghausen B. Human platelet 5-HT2 receptor binding sites re-evaluated: A criticism of current techniques corrected. Journal of Neural Transmission. General Section 1993;92(1):11–24.  

Thies-Flechtner K, Müller-Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Pharmacopsychiatry 1996;29(3):103–7.  

Thies-Flechtner K, Weigel I, Müller-Oerlinghausen B. 5-HT uptake in platelets of lithium-treated patients with affective disorders and of healthy controls. Pharmacopsychiatry 1994;27(Suppl 1):4–6.  

Tondo L, Abramowicz M, Alda M, Bauer M, Bocchetta A, Bolzani L, Calkin CV, Chillotti C, Hidalgo-Mazzei D, Manchia M, Müller-Oerlinghausen B, Murru A, Perugi G, Pinna M, Quaranta G, Reginaldi D, Reif A, Ritter P, Rybakowski JK, Saiger D, Sani G, Selle V, Stamm T, Vázquez GH, Veeh J, Vieta E, Baldessarini RJ. Long-term lithium treatment in bipolar disorder: Effects on glomerular filtration rate and other metabolic parameters. International Journal of Bipolar Disorders 2017;5(1):27.  

Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, Lewitka U, Licht RW, Manchia M, Müller-Oerlinghausen B, Nielsen RE, Selo M, Simhandl C, Baldessarini RJ. Clinical use of lithium salts: Guide for users and prescribers. Int J Bipolar Disord 2019;7(1):16.  

Ulrich G, Frick K, Stieglitz RD, Müller-Oerlinghausen B. Interindividual variability of lithium-induced EEG changes in healthy volunteers. Psychiatry Research 1987;20(2):117–27.  

Ulrich G, Herrmann WM, Hegerl U, Müller-Oerlinghausen B. Effect of lithium on the dynamics of electroencephalographic vigilance in healthy subjects. Journal of Affective Disorders 1990;20(1):19–25.  

Wolf T. Die Rolle der kognitiven Verhaltenstherapie in der Langzeitprophylaxe. In: Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Nutzen, Risiken, Alternativen, 2nd ed. Springer, Berlin-Heidelberg-New York; 1997, pp. 528–34. 

Wolf T, Müller-Oerlinghausen B. The influence of successful prophylactic drug treatment on cognitive dysfunction in bipolar disorders. Bipolar Disorders 2002;4(4):263–70.  

Wolf T, Müller-Oerlinghausen B, Ahrens B, Grof P, Schou M, Felber W, Grof E, Lenz G, Nilsson A, Simhandl C, Thau K, Vestergaard P, Wolf, R. How to interpret findings on mortality of long-term lithium treated manic-depressive patients?! Critique of different methodological approaches. Journal of Affective Disorders 1996;39(2):127–32.

 

July 15, 2021