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Given the broad human exposure to parabens, further efforts to expand this investigation to other parabens and populations are warranted. In addition to food additives, agrochemicals that contaminate food have been linked to obesity in animals and in humans. This topic has been intensively reviewed elsewhere 67 and will be summarized here. One very important example is the well-known organochlorine pesticide dichlorodiphenyltrichloroethane DDT. DDT was shown to be obesogenic in rodent models, and its effects were dependent upon the timing of exposure and gender.

Perinatal exposure of mice to DDT reduced energy expenditure and transiently increased body fat content in female offspring Moreover, ancestral exposure to DDT lead to obesity and metabolic abnormalities in male and female rats from the F3 generation, characterizing a transgenerational obese phenotype Human studies have also reported that perinatal exposure to DDT is associated with increased obesity risk during childhood and adult life The major breakdown product of DDT, p,p-dichlorodiphenyldichloroethylene DDE was associated with weight gain in multiple human studies The use of DDT was banned under the Stockholm Convention but it persists in the environment and continues to be used for malaria control in Africa.

Methoxychlor was intended to replace DDT, but was shown to induce obesity in rats Several other pesticides have been identified as being actually, or potentially obesogenic. The neonicotinoid insecticide, imidacloprid induced 3T3-L1 preadipocytes to differentiate into adipocytes and promoted obesity in mice exposed to a high-fat diet The widely used and controversial herbicide, glyphosate, induced obesity in F2 and F3 offspring of F0 female rats exposed during gestation Many other agrochemicals induced adipogenesis in 3T3-L1 preadipocytes and in mouse and human MSCs 75 , 76 , While the potential of these chemicals to promote obesity, in vivo , remains unexplored at present, the next chemical found to induce adipogenesis in cell models but that fails to promote obesity, in vivo , will be the first.

The intensive use of agrochemicals worldwide and the ubiquitous human exposure via food consumption indicates that it will be important to undertake appropriate studies in human cohorts and in animal models to understand the magnitude of the potential risk posed by these chemicals. As a result of public demand for BPA-free plastics, industry has responded by producing a variety of BPA relatives for use in plastics and in thermal papers.

These are coming into widespread use as industry strives to produce products with similar physicochemical properties to BPA-based plastics while not totally disrupting current manufacturing processes Much less is known about the potential EDC effects of these BPA analogs, although some of them have been described as obesogens in vitro and in animal models, and associated with increased body mass in humans Perinatal exposure to BPS also elicited obesity in mice A longitudinal birth cohort study revealed that BPS and BPF were significantly associated with obesity in children ages 6—19 , whereas BPA and total bisphenol levels were not significantly associated In contrast, levels of BPA have been significantly associated with obesity incidence, whereas levels for BPS and BPF were not linked with obesity in a cross-sectional study of adults after adjusting for lifestyle and socioeconomic factors While it is clear that TBT exposure can lead to obesogenic effects, it remains unclear to what extent the human population is exposed.

However, there is no question that humans are widely exposed to organotins, in general. Unexpectedly, while TBT does not elicit changes in glucose homeostasis, the offspring of DBT-exposed dams were insulin resistant Thus, while DBT can activate similar nuclear receptors as does TBT, it clearly engages additional or alternative cellular mechanisms to elicit insulin resistance. While the obesogen hypothesis was initially controversial when first proposed in , studies around the world have supported the model and it is becoming evident that obesity is considerably more complex than a simple function of energy balance.

Much has been learned about the number and types of obesogens but we need to know much more to assess their overall significance in obesity susceptibility. For example, relatively little is known about how obesogen exposure interacts with macro and micro-nutrients in the diet to promote obesity. Obesogens can affect composition of the microbiome , and transfer of an obese microbiome itself can cause obesity Very little is known about how obesogen-elicited changes in the microbiome can contribute to obesity.

A combination of mechanistic studies in cell and animal models together with longitudinal epidemiological and biomonitoring studies in humans will be required for a full assessment of the risks and costs of EDC and obesogen exposures to public health. While current estimates only consider a few chemicals for which adequate data sets are available, the costs are predicted to be substantial , Nearly all studied obesogens exert sexually dimorphic effects. For example, prenatal exposure of pregnant F0 dams to TBT produced increased fat mass in both sexes of the F1 generation, but obesity was only found in males of F2—F4 generations 96 , , The synthetic estrogen, diethylstilbestrol, the first chemical to be reported as an obesogen, in vivo , elicited obesity after perinatal exposure adult female but not male mice Many examples of obesogen exposure producing sexually dimorphic effects in animal models exist reviewed in Relatively little is known about the etiology of these sexual dimorphisms beyond some indications that effects of environmental estrogens may be expected to be more pronounced in females.

Notably, while the incidence of obesity is increasing in both sexes in human populations, obesity is significantly more prevalent in females, particularly in the USA Appropriate strategies for intervention and prevention will require a deeper understanding of what cellular pathways mediate obesogen action. A persistent difficulty in the EDC field is to understand the effects of mixtures. For example, Will exposure to combinations of obesogens result in additive or synergistic effects?

Since many obesogens appear to induce a variety of effects other than obesity, they may be acting through multiple mechanisms. Some evidence suggests that these changes in chromatin architecture can be transmitted across generations, but the mechanisms remain obscure. A handful of chemicals are known to elicit transgenerational effects on obesity, but we know relatively little about how these effects may be transmitted across generations reviewed in , Nuclear receptor activation can lead to epigenetic alterations , , but there is currently no evidence that nuclear receptor activation is a key component of the mechanism through which obesogens act across generations.

It is possible that exposure to a combination of obesogens, each of which may act through a different pathway, will be required to explain the obesity pandemic. In support of this possibility, it is well-known that chemical mixtures can induce higher receptor activation or stronger phenotypes , , , Moreover, the potential of many other obesogens to induce transgenerational obesity remains to be explored.

While much has been revealed about the number and nature of obesogens and some inroads have been made on mechanisms of action, we still know little about the entire spectrum of possible obesogens, how they act and who is exposed to what degree.

Understanding how obesogens act will facilitate the identification of other obesogens that may have similar mechanisms of action. It will be crucial to develop and deploy screening assays that are sensitive and reliable enough to identify potential EDCs and obesogens before widespread exposure and adverse outcomes occur, as has been previously discussed These are widely and frequently touted as the future of such screening studies but evidence is growing that the assays may not be sensitive or reliable enough to make effective predictions The European Union has adopted a different approach.

Under its Horizon grant program, the EU has funded eight international consortia that aim to establish standardized, internationally harmonized screening methods for EDCs. Three of these consortia are focused on developing methods to identify metabolism disrupting chemicals, including obesogens.

Since the assays to identify EDCs will be developed by experts in the field, rather than using repurposed screening assays from the pharmaceutical industry, it is likely that these efforts will bear fruit. Identifying the full spectrum of obesogens and understanding their mechanisms of action will reveal how we can best prevent exposure or reduce the effects of exposure.

Currently, little is known about the magnitude of the obesogen effect in humans, and to what extent it contributes to the obesity pandemics. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. Endocr Connect. Published online Jan 6. Author information Article notes Copyright and License information Disclaimer. Correspondence should be addressed to B Blumberg: ude.

Received Dec 7; Accepted Jan 6. This article has been cited by other articles in PMC. Abstract Obesity is now a worldwide pandemic. Keywords: obesogen, endocrine-disrupting chemical, EDC, transgenerational, adipogenesis, obesity. Introduction The incidence of obesity around the world has tripled since the s, affecting more than million people 1. The intrauterine environment and predisposition to obesity Environmental stressors experienced during fetal development can have profound effects later in life.

Endocrine-disrupting chemicals The endocrine system ultimately modulates function in tissues that regulate weight and metabolism. Tributyltin the model obesogen Tributyltin TBT was among the first obesogens to be identified and is currently the most thoroughly studied. Obesogens, old and new A variety of chemicals have been demonstrated to be obesogenic in animal studies. Table 1 Verified obesogens with possible mechanisms of action and effects.

Open in a separate window. Table 2 Potential obesogens with possible mechanisms of action and effects. Acrylamide Acrylamide is found in foods and can be formed as an unintentional byproduct of frying, baking, or roasting; this is likely to be the most common source of human exposure Nonylphenol Nonylphenol is the main microbial degradation product of alkylphenol ethoxylate, a nonionic surfactant used to manufacture a wide range of products, such as plastics, pesticides, and cosmetics Parabens Parabens are used as preservatives in pharmaceuticals, food, and cosmetic products due to their antimicrobial and antifungal properties.

Pesticides In addition to food additives, agrochemicals that contaminate food have been linked to obesity in animals and in humans. Other bisphenols As a result of public demand for BPA-free plastics, industry has responded by producing a variety of BPA relatives for use in plastics and in thermal papers.

More organotins While it is clear that TBT exposure can lead to obesogenic effects, it remains unclear to what extent the human population is exposed. Future directions While the obesogen hypothesis was initially controversial when first proposed in , studies around the world have supported the model and it is becoming evident that obesity is considerably more complex than a simple function of energy balance.

Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. References 1. New England Journal of Medicine Prevalence of obesity and trends in the distribution of body mass index among US adults, — JAMA Report Prevalence of childhood and adult obesity in the United States, — The carbohydrate-insulin model of obesity: beyond "calories in, calories out".

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Acrylamide induces adipocyte differentiation and obesity in mice. New discoveries in the neurosciences, refined technical advances in psychotherapy, and a large number of outcome studies in both pharmacotherapy and psychotherapy have made it abundantly clear: People are complex. Mental health problems spring from many sources; and reductionist, unidimensional models are simply inadequate to explain the wide array of mental and emotional problems people experience.

Likewise, no single approach to treatment works for all problems. Certain disorders clearly respond better to certain interventions, whereas others require alternative approaches. In writing this book, although our primary focus is on psychopharmacology, we share a strong respect for what will be termed integrative approaches to treatment: recognition of the importance of varied treatments and collaboration among profes- sionals from different disciplines.

We hope that you will find this book helpful as you engage in this most important profession and work toward the goal of reducing emotional pain. History of Biological Psychiatry In understanding psychopharmacology, it may be helpful if you are able to place it in a historical context.

Let's take a brief look at this history as it unfolded. In the late eighteen hundreds, psychiatry was clearly rooted in the medical model and the neurology of the day. Psychiatrists believed, almost exclusively, that mental illness could be attributed to some sort of biologic disturbance.

The earliest attempts to approach the understanding of mental illness in this era involved two main areas of investigation. On one front was the development of the first systematic nosologic system by Emil Kraepelin. And many of Kraepelin's original notions about the classification of major mental illness have stood the test of time. He was a brilliant investigator and the one most responsible for ushering in descriptive clinical psychiatry. However, his endeavors must have been accompanied by a good deal of frustration and impotence, since, despite the develop- ment of a systematic approach to diagnosis, Kraepelin and other psychiatrists of his time had few, if any, methods of treatment.

At the same time, the hunt was on for evidence of brain pathology, which was presumed to underlie mental illness. Research was conducted in neuroanatomy labs but yielded few concrete results. For example, the famous French neurologist Jean- Martin Charcot believed that hysterical conversation symptoms were undoubtedly due to some type of central nervous system lesion. He explained the fact that no demonstrable pathology could be isolated on autopsy by saying it simply suggested that somehow the lesion mysteriously disappeared at the time of death.

We must bear in mind, however, that in all likelihood, these researchers and clinicians were desper- ate to find causes and cures and went at it by the means best known to them biology and using the scant technology available at the time. Biological psychiatry got a shot in the arm in the late eighteen hundreds, as two discoveries were made. At the time, probably one half of those housed in asylums suffered from a type of psychotic-organic brain syndrome that ultimately was found to be caused by the Treponema pallidum bacteria a central nervous system infection seen in the late stages of syphilis.

It was also eventually discovered that some organic mental syndromes were due to pellagra a disease associated with niacin and protein deficiency. These were important discoveries, and they fueled enthusiasm in biologi- cal psychiatry. It was just a matter of time, it was felt, before other biologic causes 4 Handbook of Clinical Psychopharmacology for Therapists would be isolated and medical treatments developed.

However, such discoveries did not occur until the middle of the twentieth century. For practical purposes, biological psychiatry came to a halt as it entered the nineteen hundreds. The disappointments stemming from medical research on mental illness and the failure to develop any effective treatment probably increased the receptivity of psy- chiatry to divergent approaches. At this same time Sigmund Freud was assembling the basic notions of psychoanalysis. Freud's initial theory was strongly influenced by his own medical and neurological training for example, his "Project for a Scientific Psychology," , and many of his prevailing ideas continued to have their roots in biology, including drive theory, instincts, and psychosexual development.

However, his newly emerging theory and techniques of treatment sparked interest in the use of novel, nonmedical approaches to treatment. By the s psychological rather than biological explanations for the develop- ment and treatment of psychopathology had found their place in clinical psychiatry, and by the s psychodynamic thinking had permeated American psychiatry and become the dominant theoretical model.

Yet these newly developed approaches proved to be inadequate in the treatment of the more serious forms of mental illness, such as schizophrenia and manic-depressive psychosis. In one of his last manuscripts, Freud himself admitted his disappointment in psychoanalytic methods for treating schizo- phrenia.

He hypothesized that eventually it would be discovered that these grave mental disorders were due to some form of biologic abnormality, and that perhaps drugs would eventually be found to treat these illnesses. Somatic Therapies In the days of Kraepelin, pharmaceuticals were used to treat mentally ill patients. Generally, the drugs were prescribed to sedate wildly agitated psychotic patients. For example, Kraepelin listed in one of his textbooks the following group of recommended medications Spiegel and Aebi : For Agitation Opium Morphine Scopolamine Hashish To Produce Sleep Chloral Hydrate Ether Alcohol Chloroform Bromides Kraepelin noted, however, that none of these preparations cured mental illness, that they were for short-term use, and that a number of them could lead to problems with addiction.

All of these drugs achieved behavioral control by sedating patients; none really affected psychotic symptoms per se, nor did they have any impact on activating patients who were stuporous or clinically depressed. Other somatic therapies were developed in the first half of the twentieth century, with variable results.

Malaria therapy was conceived in , insulin shock in , psychosurgery in , and electroconvulsive treatment ECT in All of these methods, as originally conceived, carried serious risks, and most demonstrated mar- ginal effectiveness. Psychosurgeries were carried out by the thousands in the s, resulting in rather effective behavioral control over agitated psychotic patients but at Introduction 5 great human cost.

Many, if not most, lobotomized patients were reduced to anergic, passive, and emotionally dead human beings. Electroconvulsive treatment, conversely, was quite effective in certain groups of patients, such as those with psychotic depressive disorders. However, early methods of administration were fraught with dangerous complications and side effects, and ECT was used on a widespread basis, indiscriminately. Many patients were treated with it inappropriately and did not respond.

As shall be discussed later, in recent years significant advances have been made in ECT, and it now affords a highly effective, safe treatment for selected types of patients. Most severely ill patients in the late nineteenth and early twentieth centuries con- tinued to be housed in overcrowded state mental hospitals and were "treated" using tried and true methods of the day: seclusion, restraint, and wet-sheet packs.

Although seemingly inhumane procedures were employed, it may be important to consider that the psychiatrists of that era were relatively helpless in the face of very severe mental illnesses and that these approaches although certainly misused at times reflected their attempt to reduce the horrendous human suffering seen in thousands of severely ill people.

New Discoveries In the s, three new discoveries heralded the beginnings of a new interest in biological psychiatry. Interestingly, these three areas of investigation were conducted by separate groups of researchers, each with little knowledge of the work being done by their colleagues Kety Thorazine and other early psychotropic drugs Immediately after World War II, medical researchers and chemists working for pharmaceutical companies were trying to develop a drug that would reduce the com- plications associated with shock following major surgery.

In early , a compound initially labeled RP was developed and testing with surgical patients was begun Spiegel and Aebi The initial results were encouraging. Given preoperatively, it relaxed patients, somewhat reduced postoperative shock, and proved to be a good antiemetic preventing postsurgical nausea.

The finding that it produced noticeable sedation came as a surprise. In the aftermath of field trials with surgical patients, the pharmaceutical company Laborit decided to try this medication with restless, agitated psychiatric patients to help improve sleep, totally unaware that the drug would prove to have more widespread effects on the psychiatric patients who were tested. Initial clinical trials first reported in resulted in marked behavioral changes when given to manic and schizophrenic patients.

Not only did it produce a calming effect, but after a period of time it actually appeared to reduce psychotic symptoms, such as delusions and hallucinations. Additional studies were carried out the follow- ing year, and by the drug was approved for use. The new medication was given the generic name chlorpromazine; in the United States it was marketed under the brand name Thorazine.

It received immediate acceptance, and by the end of , for the first time ever, there was a marked decrease in the number of patients incarcerated in state mental hospitals: the first major breakthrough in psychopharmacology. Other psychotropic medications were discovered during the s.

The first anti- depressant was developed in iproniazid, an MAO inhibitor , although clinical studies in humans did not take place until The first tricyclic antidepressant, imipramine Tofranil , was developed in and entered the market in The first 6 Handbook of Clinical Psychopharmacology for Therapists minor tranquilizer, meprobamate, was released in , followed shortly by the safer benzodiazepine, chlordiazepoxide Librium , in Finally, lithium carbonate, origi- nally used as a sedative by J.

Cade in , began to be used to treat bipolar disorder formerly called manic-depressive illness in the early s. It is interesting to note that most of these psychopharmacological discoveries were accidental; that is, the drug companies were developing medications to treat other medical illnesses and just happened to find that the drugs could affect psychiatric symptoms. Also, these discoveries were made empirically; they were not developed as an outgrowth of a particular theory of neurochemical dysfunction, nor was the mech- anism of action at all known.

What was evident was that the medications worked and were far superior to any previous treatments for severe mental illness. The synapse and neurochemical transmission Although C. Sherrington inferred the existence of the synapse the small space separating individual nerve cells as early as , the specific details of synaptic transmission were not fully understood for many decades thereafter. Sherrington's ideas involved a sort of telephone switchboard model of the nervous system, and neu- ronal messages were assumed to be transmitted via electrical stimulation.

It was not until the s that neuroscientists realized that communication between nerve cells, although partially electrochemical in nature, is largely due to the release of chemical substances. These chemicals, which transmit messages from one nerve cell to another, are referred to as neurotransmitters; other chemicals that play an indirect role in neurotransmission are called neuromodulators. With this discovery, it became possible to imagine that certain neurologic dys- functions might be caused by chemical irregularities, and that therefore it might be possible to develop drugs that could influence or alter neurotransmitter function.

Genetic studies The third line of investigation involved both genetics and studies of familial pat- terns of mental illness. The earliest research in this direction was ultimately criticized for numerous methodological flaws. Yet some of the basic findings proved to be fun- damentally correct. There is a strong genetic loading for certain mental illnesses, in particular for schizophrenia and bipolar disorder.

Controversy By the early s then, it had been discovered that synaptic activation is chemi- cal in nature; certain illnesses seem to be genetically passed on from generation to generation and genetic factors are expressed biochemically ; and newer drugs could significantly reduce psychiatric symptoms.

The triangulation of this data provided rather strong support for a renewed interest in biological psychiatry. There was new hope for the millions of patients suffering from serious mental illness, and psychiatry had begun to step back into "real medicine" again. However, despite the advances, these new treatments were plagued by a host of side effects — some unpleasant, some actually dangerous.

These potent drugs were also often overused or were misused in certain treatment settings. Consequently, Introduction 7 Medications and the Media Research studies and clinical experience certainly influence prescribing practices.

However, in recent years the media has had a profound effect on public opinion and ultimately on clinical practice. Andrew Brotman, sum- marizing the work of Safer and Krager , states, "The media attack was led by major national television talk show hosts and in the opinion of the authors, allowed anecdotal and unsub- stantiated allegations concerning Ritalin to be aired.

There were also over twenty lawsuits initi- ated throughout the country, most by a lawyer linked to the Church of Scientology" Brotman , audiotape. In a study of the effects of this negative media and litiga- tion blitz, conducted in Baltimore County, Maryland, Safer and Krager found that the use of Ritalin had dropped signifi- cantly.

From through , the use of Ritalin had increased fivefold. However, in the two-year period during and just follow- ing the negative media attention, there was a 40 percent decrease in prescriptions for Ritalin. And this decrease occurred at a time when research on ADHD and stimulant treatment continued to strongly support the safety and efficacy of such medications. The authors go on to state that 36 percent of children who discontinued Ritalin experienced major academic maladjustment such as failing grades or being suspended , and an additional 47 percent who continued controversy began to arise, both among profession- als, and in the lay public and mass media.

Professional dissention Within professional ranks, debate issued from two fairly discrete theoretical camps: those who were promedication and those who were pro- psychotherapy. Each group amassed impassioned arguments not only in favor of its own point of view, but also against the other school of thought, as set out below. Likewise, the reductions of drive strength afforded by some psychotropic medica- tions may operate to free up more psychic energy, which could then be channeled into adaptive ego functions.

Thus medications are much more cost- effective and more readily available to the general public. Finally, those strongly wedded to a biochemi- cal model of psychopathology contended that social, behavioral, and psychological approaches simply could not correct the underlying biologic abnormality responsible for major mental illnesses. Recent studies, however, have cast doubt on this hypothesis. Medications only treat symptoms, whereas psychotherapy focuses on the whole person or psyche.

The pre- scription of medications may, at least at an unconscious level, communicate the message that the drug will do the work, you don't have to. Numerous documented instances of overuse of tranquilizing medications to achieve behavioral control provided fodder for this argument. Concurrently, as Ritalin use especially new prescriptions decreased, there was a significant fourfold increase in the pre- scription of tricyclic antidepres- sants among ADHD children. It is important to note that tricyclics, although often used to treat ADHD, tend to have more troublesome side effects than Ritalin, and have been implicated in six reports of cardiac fatalities.

Brotman concludes, "When there are reports in the media that lead to stigmatization of a certain drug. The negative atten- tion was sparked by a single article Teicher, Clod, and Cole documenting the emer- gence or reemergence of suicidal ideas in six patients treated with Prozac. The six patients had been diagnosed as suffering from severe depressive disorders, and in no case were there actual suicide attempts following the onset of treatment with Prozac.

But suddenly Prozac was thrust into a very unfavorable light and was the next drug in line to find itself the topic of television talk shows. Subsequent studies have failed to find any evidence that Prozac is more likely to be associated with suicidal feelings than any other antidepressant Fava and Rosenbaum ; Beasley and Dornseif In fact, in one study the incidence of suicidal continued Introduction 9 Although this debate continued throughout the s and s, clearly there were also a number of what G.

Klerman Beitman and Klerman calls "pragmatic practitioners" — those mental health professionals who used whatever approaches seemed to work. Certainly it was, and is, reasonable to consider that some disorders are best treated by psychotropic medications, others by psychotherapy, and it often makes sense to use a combination of both modalities. Public opinion A parallel to the professional debate began to occur within the general public. In institutes of higher education, the humanistic movement began to permeate not only departments of psychology but the global academic community as well.

The post-McCarthy social climate was ripe for new atti- tudes that challenged political and social control and applauded the expression of free will, self- expression, and self-actualization. Reports began to surface regarding the abuse of psychiatric medi- cation by the medical profession. Opponents to drug treatment accused the psychiatrists of using medications to achieve control.

The term "chemical straitjacket" became popularized. The s saw the proliferation of new tran- quilizers, and pharmaceutical companies reaped fortunes from the sale of well-known pills such as Valium and Librium. The vast majority of prescrip- tions written for minor tranquilizers more than 90 percent were written by family practice doctors, not psychiatric specialists. The "drugged state" was the fastest growing state in the union Bly The inappropriate use and abuse of tranquilizers gained increasing public attention and even found its way into popular songs the Rolling Stones' "Mother's Little Helper" and movies I'm Dancing as Fast as I Can.

In the s, the Church of Scientology was successfully sued by the American Psychiatric Association. In retaliation, it began a long, embittered assault on American psychiatry. Initially the Church of Scientology launched a negative campaign against the use of Ritalin, a psychotropic medication used to treat attention-deficit disorder. More recently it has orchestrated a move to shed negative light on the antidepressant Prozac see sidebar on page 8.

Biological psychiatry was under attack. Although clearly there was a good deal of abuse and misuse of psychoactive drugs, there also continued to be decreasing numbers of people living in mental hospitals, and drug companies were at work developing newer and "cleaner" psychotropic medications, medications with fewer side effects. However, the FDA ruled against taking such action because there was no scientific evidence to support the claims made by the Church of Scientology Burton All medications produce some side effects.

Reports of adverse effects, even if very infrequent, must be taken seriously and investigated systematically. There is a place for skepticism and scrutiny. However, one must consider the negative effect of unsubstantiated reports in the lay press. For example, the risk of Prozac-induced suicide appears to be extremely low, and the suicide rate in untreated major depres- sion is reported to be 9 percent.

Clearly, failure to treat carries the graver risk. It is very likely that many seriously depressed people and parents of ADHD children have been understandably, and unnec- essarily, frightened by negative, sensationalistic reports in the media. To quote Brotman again, "Pharmacotherapy does not exist in a social and political vacuum.

Compounds introduced in the s and early s have yielded effective medications with much more user-friendly side-effect profiles. This greatly increases the psychiatrist's arsenal of effective medications. These technologies have been able to isolate localized brain abnormalities in certain mental disorders, including major depression, schizophrenia, ADHD, and obsessive-compulsive disorder.

They can provide data on particular sites of drug action or binding, and can illustrate Psychopharmacology and the "Managed Care" Dilemma Since the advent of newer- generation psychotropic medica- tion, many millions of people are receiving more effective treatment for a host of psychiatric condi- tions.

For this we are grateful. However, it also has become abundantly clear that the effects of psychiatric drugs are limited. Under the best of all circum- stances such treatments do not have an impact on all aspects of psychological suffering. In our view, successful psychiatric treatment should always include psychotherapy.

Only in the context of a healing relationship may many aspects of psychological dysfunction be adequately addressed. Numerous interpersonal, intrapsychic, spiri- tual, and existential dimensions of human functioning simply are not amenable to pharmacologic treatment. In this book we acknowledge the many benefits of drug treat- ment; however, we must also share a concern: In these days of cost containment and managed care, individual human lives and quality-of-life issues are often ignored.

It is a real concern that an automatic, knee-jerk reaction will be just to prescribe pills, when so much more is needed. We are treating people, not just nerve cells. However, given the rising cost of pharmaceuticals, the most recent cost-containment strategies are as likely to focus on the use of psychiatric medication as well as on psychotherapeutic inter- ventions.

Paradoxically, perhaps as psychotropic drugs begin to account for an ever-increasing percentage of total health care expenditures, we will see best- practice guidelines influenced continued Introduction 11 changes between the pre- and post-treatment status of particular brain structures. Imaging techniques have added considerable "hard data" to various theories of biochemical etiol- ogy in selected mental illnesses. Although early psychopharmacology was implemented without any real knowl- edge of the underlying pathophysiology, in the past decade, biochemical theories have gained tremendous scientific support.

These new developments in psychiatry and the neurosciences have been hard to ignore. Many formerly hard-line psychotherapists have been won over by the flood of research findings and their personal experiences in treating people with psychoactive drugs. During this same period, important advances were made in the theory and practice of psychother- apy. During the late s and s the first truly well-controlled psychotherapy studies emerged including the now popular meta-analyses.

The results of these studies cast doubt on the findings of early research that had suggested that psycho- therapy was ineffective Eysenck , for example. Of the many forms of psychotherapy that have been developed, the meta-analyses suggest that no single school of therapy is clearly superior and that psychotherapies across the board are often much more effective than no treatment.

Also during this time we witnessed the devel- opment of novel treatment approaches, such as cognitive behavioral psychotherapy Beck and interpersonal psychotherapy Klerman et al. These approaches have appeal, in that they can be somewhat systematically applied some even provide "canned" formats or "cookbooks".

Also, the methodology is a bit less reliant on the personal characteristics of the therapist. These approaches then lend themselves to a short-term format and can often be conducted in groups. And, finally, these psychotherapies can be more easily studied.

Both cognitive behavioral and interpersonal psychotherapies have a solid track record of effectiveness as is dis- cussed further in the next chapter. Finally, both clinical-anecdotal and research studies have emerged that support the combined use of pharmacotherapy and psychotherapy in the treatment of par- ticular disorders.

At times, the combined treatments have been shown to be superior to either single treatment alone. We hope that critical ques- tions will be raised. Are medication treatment failures completely an effect of the drugs not working? Or could the rela- tive lack of psychotherapeutic modalities be a contributing factor?

Similarly, as the prescrib- ing of psychotropics has become the first step in treatment, has that first step been taken before an accurate diagnosis was made? Are we medicating out of habit, when it is not really indicated? If the patient would benefit more from psychotherapy, are we doing more harm than good?

We remain hopeful that the pendulum will swing back to support what most practicing clinicians know to be true: the best outcomes result from appropriately balanced treat- ment that includes therapy and medications.

Human beings and their life problems are enormously complex. And it is the highly trained clinician who must ultimately decide which com- binations of treatments are best suited for each individual client not insurance companies, treatment manuals, or untrained technicians!

As we shall be discussing in subsequent chapters, current evidence suggests that particular disorders do respond best to certain medical treatments, and for these, medications are the treatment of choice. Other disorders have little to do with biochemical dysfunction, and medications play little or no role in their treatment. And still other disorders require the skillful integration of biological and psychotherapies.

As the saying goes, when you only have a hammer, every problem looks like a nail. Fortunately, at the present time, mental health professionals have access to a "toolbox" of approaches that can, if employed appropriately, dramatically increase our effectiveness in reducing emotional suffering and promoting mental health. Why Learn About Psychopharmacology? In the United States, the majority of mental health services are provided by nonmedi- cal therapists.

Likewise, the majority of prescriptions for psychotropic medications are written by family practice and primary care physicians see figure 1-A. Thus, even though psychiatrists represent the branch of medicine that specializes in psychophar- macology, they are directly responsible for providing only a fraction of professional services to the mentally ill. Consequently, it is becoming increasingly important for all mental health clinicians to have a basic familiarity with psychiatric medication treatment.

Many nonmedical psychotherapists are or will become strongly and rather directly involved in medication treatment. In some settings psychologists and social workers assume a major role in monitoring client responses to psychotropic medications. As primary therapist, these practitioners are in most frequent contact with clients and are in the best position to observe symptomatic improvement, side-effect problems, and issues involving medication compliance.

When consulting with primary care physi- cians, or as a staff member in some FIMO settings, nonmedical therapists who are well-versed in the use of psychiatric medications can play an active albeit collabora- tive role in recommending particular medications and dosage adjustments. Currently, properly trained psychologists can become licensed to prescribe psychiatric medications in the states of New Mexico and Louisiana. These various activities reflect quite direct involvement in medication treatment by nonmedical therapists.

In contrast, many nonmedical therapists have little to do with drug treatment. In some cases this may be due to the nature of their position in a particular treatment setting; in others it may have more to do with their own preferences and biases, such as opposition to medication treatment.

However, we believe that, regardless of the degree of involvement and interest in medication treatment, it is increasingly impor- tant that all mental health therapists become acquainted with some basic notions regarding psychopharmacology.

Convincing evidence now exists that certain mental disorders are either caused or accompanied by neurochemical abnormalities. The failure to appropriately diagnose and medically treat such conditions can result in the use of ineffective or only par- tially effective treatments and hence in prolonged suffering. Aside from the obvious cost in human terms, prolonged inappropriate treatment results in excessive financial burdens for clients, their families, and the health care system.

In addition, to date there have been successful malpractice suits brought against therapists who failed to treat or refer for treatment patients suffering from particular disorders known to be generally responsive to medication. All mental health professionals must be able to, at the very least, diagnose mental disorders that require psychotropic medication treatment so that appropriate referrals can be made.

Differential diagnosis will be discussed in detail in this book. In many cases, clients may not choose to see a psychiatrist, even when told by their therapists that medication treatment is indicated. This may be due to financial concerns or to the negative stigma some people believe is attached to psychiatric treat- ment. A viable alternative, in some cases, is referral to the family practice doctor. Many people suffering from emotional distress see their family physician first.

This doctor may begin treatment with psychotropic medications and may also refer the patient for psychotherapy. In such cases, the nonmedical therapist may be in a key position to supply information regarding diagnosis and treatment response.

Increasingly, family practice physicians and nonmedical therapists become partners collaborating on the treatment of many clients — especially those suffering from fairly uncomplicated depressive and anxiety disorders. Effective consultation with family practice doctors and psychiatrists alike is enhanced by the nonmedical therapist's ability to accurately communicate and discuss diagnosis, target symptoms, presumed etiology, and possible treatments.

We hope this book will provide a solid grounding in basic issues to help improve communication and cooperation between professionals. Mental health treatment has moved increasingly toward greater acceptance of multidisciplinary and integrated treatment modalities.

As sophistication in the diag- nosis and medical treatment of mental disorders continues to develop, it will be impor- tant that mental health professionals not take a step backward. The polarization of models and professional "turf battles" of the s and s may have sparked useful and lively debate, but they also often resulted in a fragmentation of care.

Ongoing knowledge of and respect for diverse models and collaborative involvement hold promise for increasingly effective efforts in treating mental illness. Unfortunately, often the decision is based largely on the clinician's a priori view toward treatment, deriving from his or her theoretical perspective. As we shall argue, the critical variable in this decision is more appropriately based on the diagnosis, and in particular on the pres- ence or absence of key target symptoms that suggest the patient is experiencing some form of neurochemical disorder.

In broad and extremely heterogeneous groups of disorders, such as mood dis- orders, some may be largely or exclusively caused by biological factors. Other disor- ders in such groups share some symptoms with biologic-based mental illness, yet their etiology stems largely or exclusively from nonbiologic sources, for example, emotional, psychosocial, or cognitive sources. Thus a very important question to address when making a diagnosis and subsequent decisions about treatment is, "Is there any evidence to suggest that this person's problems are due to some form of biologic disturbance?

Invariably, there is a complex interaction between psychological and biological factors in all cases of emotional disorder. This complexity will be the focus of this chapter. Psychology and Biology: A Two-Way Street A comprehensive discussion of the classic philosophical issue, mind-brain dualism, is beyond the scope of this book. The reader is referred to Goodman ; Young However, we would like to highlight a small number of cases and research studies that illustrate the interactive effects of biologic and psychologic factors.

Biological Factors' Impact on Psychological Functioning Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs, and fears It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness, and acts that are contrary to habit.

Early physicians were keen to note that brain injuries could result in profound changes in personality, cognition, and emotional control. And, as noted in chapter 1, in the earliest days of modern psychiatry the field was grounded in biological sciences and the medical model. Two fairly common clinical examples serve as illustrations of how disordered brain functioning can lead to marked psychiatric symptomatology.

Case 1 Robert B. He has always been an ambitious, bright, energetic man. Despite normal stresses of daily life, he had never experienced major psychiatric problems until a month ago. For no apparent reason he began gradually to slip into a state of lethargy, fatigue, and low motivation. His normal zest for life diminished, his usual sharpness of wit became dull, and his sense of enthusiasm gave way to increasing blandness and emptiness. He was totally perplexed as he searched his recent life experiences to find the cause for his malady.

None was to be found. In the ensuing weeks he lost weight, frequently woke at A. Upon close investigation by his family physician, it was eventually discovered that the depressive symptoms began several weeks after he had started taking an antihypertensive drug to treat his high blood pressure. The medication was suspect and was eventually changed. Within a couple of weeks, the depression vanished. This case illustrates how a medication can, at times, dramatically alter a person's brain chemistry, resulting in major psychiatric symptoms.

In Robert's case, there was no evidence of long-standing psychological problems and no clear psychological stressors. The brain can be seen, in a sense, as a tremendously complex biological ecosystem. As in other ecosystems, global functioning and survival depend on a large number of interrelated variables.

At times, small changes in one aspect of the system influ- ence a number of other variables — in essence, sending a ripple effect throughout the entire system. In the brain, often certain delicately balanced neurochemical systems can be altered the term often used is dysregnlated , resulting in a cascade of alterations affecting many other neurochemicals and the functioning of a host of brain struc- tures.

A drug, as in the example above, is but one of many variables that can result in neurochemical dysregulation and resulting psychiatric symptoms. More will be said about other causes later in the chapter. However, during the past three months she became unable to tend her garden for more than a few minutes at a time.

She was almost constantly seized by tremendous restlessness and agitation, fretting, wringing her hands, and pacing about her house. Elizabeth lost twenty-five pounds over this three-month period and suffered fitful sleep. She also began to contemplate suicide.

Her hopes for a well-deserved, peaceful retirement seemed to have been erased, as if she were plagued by some kind of curse. She could pinpoint absolutely no painful life events that might give meaning to her condition. Fortunately, ultimately it was discovered that she was suffering from hyperthyroidism. Following successful treatment, she has been able to return to her garden and her life. In this case, a metabolic disorder was the culprit. In the cases of both Robert and Elizabeth, neurochemical and hormonal factors grossly interfered with brain function- ing.

In both cases, the people were radically changed. Their perceptions were altered pessimism, hopelessness , their sense of self was shaken, their emotions were out of control, and their physiological functioning had been derailed. Certainly they had strong emotional reactions to these changes a phenomenon sometimes referred to as secondary emotional symptoms ; however, in both cases the primary etiology was biological. A11 mental health clinicians will encounter clients who present for treatment with presumed psychological problems but who, in fact, are suffering from biologically based disorders.

For example, for hundreds of years it has been noted that severe stress can lead to disease. Family physicians have long noted that in the wake of tragic losses, the bereaved easily fall prey to illness. Yet not until this century did the psychology-biology interaction begin to be explored. Psychosomatic medicine was ushered in by the pioneering work of Franz Alexander in the s. And an explosion of interest and research has been seen in the s and s in the emerging field of 1.

The term endogenous means "arises from within. The disorders can be attributed to a biological abnormality or a predisposition or vulnerability to dysfunction. Many of the so-called endogenous disorders appear to carry a genetic loading: they are passed from generation to generation and presumably can be linked to certain genetic factors. More will be said about endogenous psychiatric disorders in subsequent chapters.

Integrated Models 17 psycho-neuro-immunology — the study of the effects of emotional factors on disease susceptibility and disease resistance. It would require several textbooks to even begin to review the literature in psycho- somatics and psycho-neuro-immunology. We would, however, like to briefly discuss a few studies that shed some light on the issue of the interaction of psychology and biology and its relationship to mental illnesses.

The first two of these studies involved experimentation with animals. Kandel and colleagues have studied the effects of environmental experiences and learning on the nervous system in the Aplysia a marine mollusk. This animal is well suited for such a study because its nerve cells are quite large and easy to visualize. Also, it does respond well to learning experiments such as habituation, sensitization, and classical conditioning Pinsker et al.

The researchers were able to trace neural pathways from touch recep- tors in the mollusk's gill and siphon, through its primitive nervous system, and out into corresponding motor neurons. Using repeated exposures to mild aversive stimuli, the investigators were able to document specific biochemical changes at the synapse, as well as structural changes in specific nerve cells.

Conclusion: environmental events and learning are actually accompanied by measurable changes in nerve cells; the animal's biology is altered. In these classic studies, animals are exposed to extremely aversive conditions, from which they have no escape. After a period of expo- sure, the animals begin to exhibit marked behavioral changes: They become passive and immobile. And they fail to mount coping responses escape from later aversive situations from which escape is possible.

In many respects, the animals have learned that they are helpless to respond, and then they come to take on characteristics that resemble major depression in humans. Interestingly, not only do these helpless rats behave in a depressed manner, but their biochemical functioning is altered. Measures of brain chemistry reveal neurochemical alterations that are identical to those seen in humans suffering from severe grief reactions or clinical depression. Again, environmental expe- riences have modified brain functioning Weiss, Glazer, and Pohorecky For example, emotionally healthy individuals without a personal or family history of depression who encounter major psychosocial stressors especially losses can become depressed.

Presumably such people are not especially at risk biologically or psychologically for depression, but nonetheless they become depressed in response to significant stressful events. Further, in the course of their reaction, some patients develop not only emotional symptoms sadness, pessimism, low self-esteem but also a host of biologic symptoms, such as sleep disturbances and marked biochemical abnormalities.

The chemical dysfunctions include dysregulation of both neurotransmitters in the brain and hormones for instance, adrenal hormones such as cortisol. Metabolic by-products of neurotransmitters have been measured in assays of spinal fluid and by way of brain-imaging techniques such as PET and SPECT scanning.

PET scans allow researchers to directly image living 18 Handbook of Clinical Psychopharmacology for Therapists brain tissue and thus provide data on metabolic activity of specific areas of the brain. Studies using PET scans in severe obsessive-compulsive disorder reveal a localized brain abnormality: a metabolic disturbance in the head of the caudate nucleus, a brain structure that is part of the basal ganglia. In obsessive-compulsive disorder, when individuals are symptomatic, this abnormality is visible on PET scans.

Yet following successful behavioral treat- ment exposure and response-prevention treatments the functioning of this brain area normalizes. As a consequence of the initial episode, neurons in key areas of the limbic system may undergo a process of modification neuro- chemically and even structurally , whereby the brain is changed more or less permanently. The result of this is that, following the first one or two episodes, the altered brain functioning leaves the nervous system at much greater risk for subsequent episodes and sets in motion an endogenous process whereby affective episodes can then occur spontaneously, even in the absence of psychological stress.

From that point on, if the disorder is not controlled, each episode further affects the nervous system; the threshold for recurring episodes becomes progressively lower. This process is known as kindling. It begins as a response to external stressors and evolves into a largely biological illness. These are but a few of many studies and clinical findings that collectively provide strong support for the idea that environmental and psychological factors can signifi- cantly affect biologic and neurologic functioning.

Biological-Psychological Interactions It is very likely that complex, interactive effects exist between biological and psy- chological factors. It's never a question of all or none. In the case of Robert B. This eventually led to performance problems at work and a number of critical remarks from his boss. These events began to fuel the flame of low self-esteem.

Low self-esteem is generally not felt to be a primary symptom of biologically based depressive disorders, but it is almost universally seen to emerge as patients live with ongoing clinical depression. Biologic effects can contribute to the pessimistic thinking seen in depressive disorders and the tendency to anticipate fearful outcomes often seen in anxiety disorders.

Increased emotional arousal or pain may motivate a person to become more socially withdrawn and can often lead to a host of negative conclusions regarding personal competency, as in, "What's wrong with me? I'm crying like a baby. Such behav- ior can continue to be a source of tremendous personal embarrassment and shame long after the psychotic episode is resolved.

These consequences of a primarily biologically based mental disorder have an impact on the individual's sense of self-worth and competency in the world. Conversely, this increased level of despair can, in itself, operate to intensify the underlying biological abnormality. Practical Implications As previously mentioned, the question "Is this disorder psychological or is it biological? The more appropriate question is "To what extent is there evidence that biochemical factors may be contributing to a patient's current symp- tomatology?

To the extent that we can determine biologic etiology or at least a degree of biologic dysfunction as a part of the more global disorder , pharmacologic treatments may be indicated. How a biologic etiology and the need for medication are determined is addressed in detail in later chapters. Stimulus-Response Specificity Stimulus-response specificity is a concept describing conditions where a very specific response can be predicted with tremendous regularity when a stimulus is applied.

One example would be that an electrical shock to muscle tissue evokes a contrac- tion. This model is appropriate for some types of medical interventions. For example, for acute cardiac and respiratory arrest, the techniques of cardiopulmonary resusci- tation CPR can be used with most victims, regardless of their age, socioeconomic status, sex, or religious beliefs.

When there is an obstructed airway, performing an emergency tracheotomy is appropriate for victims regardless of their emotional status, personality style, or level of psychosocial maturity. Likewise, some medications have fairly universal effects on all people; for instance, sodium pentothal produces unconsciousness Deckert Medical treatments in psychiatry generally do not follow the rule of stimulus- response specificity.

Although the particular mechanism of drug action may be identified, the same medication given to two depressed patients, for example, may affect them very differently. Some of these differences may be traced to variations in metabolism from individual to individual see chapter 4. Or the underlying bio- chemical abnormality in one depressed patient may be different than the abnormality in another depressed patient, and thus the medications affect different underlying disorders.

Beyond these physiological differences, however, the patients' responses may be influenced to a significant degree by a host of social, cognitive, and personality factors that have little or nothing to do with biology. In the realm of psychiatric medication 20 Handbook of Clinical Psychopharmacology for Therapists treatment, sociocultural experiences and beliefs, personality style, and a vast number of personal psychodynamic factors can, and do, dramatically influence patient response.

Psychological functioning cannot be understood using the simple, reductionist notions implied in stimulus-response specificity The good clinician always treats the person, not just the disorder. We may choose to influence nerve cells with psychotropic drugs, but the response will always be woven into the complex fabric of highly idiosyncratic personality factors.

Therefore, successful pharmacologic treatment always requires a thorough knowledge of not only the diagnosis and pathology and the medications used, but the unique meaning of the treatment to the individual patient. Assembly-line psychotropic treatment often fails, not because medications are ineffective, but because clinicians do not take the time to understand their patients.

Unfortunately, in many overcrowded mental health clinics, some clinicians act as if stimulus-response specificity is appropriate. The result is that often these attempts at treatment efficiency and cost containment backfire. Many patients don't respond well and either must demand further outpatient services or continue to decompensate until they require hospitalization. And, of course, there is the human cost associated with prolonged suffering.

In the remainder of the chapter, we explore a number of ideas regarding psycho- logical factors that have direct bearing on the outcome of medication treatment. The Psychodynamics of Pharmacologic Treatment When a prescription is written and a pill is taken, the effects of the medication are almost always influenced by a number of psychological factors. Some of these factors have to do with the commonly held beliefs regarding "drugs" and "illness" that are etched into the experience of most people in our culture.

Other factors spring from highly personal, idiosyncratic sources, either in conscious awareness or buried deeply in the unconscious mind. The astute clinician should continually ask the questions, "If medications are sug- gested or prescribed, how will this be perceived by my patient? It is not like a landscaper recommending and applying a particular fertilizer to your lawn.

Rather, it can be a highly personalized communication between therapist and client, a communication ripe for all sorts of transference distortions and a type of interaction that may alter the nature of the therapeutic relationship. In addressing these issues, we will first speak about rather common, generic themes and then go on to describe more unique, personal concerns.

Let's consider some of the possible consequences. Generic Meanings In our culture, certain themes are evident in our cliches and language that link the taking of medicine with badness and punishment. The saying "Give him a taste of his own medicine" is but one example.

One of the classic scenes from the Our Gang movie shorts has the wicked stepmother punishing Spanky and Alfalfa by making them swallow castor oil. Hearing bad news or carrying out unpleasant tasks is sometimes Integrated Models 21 referred to as having to "swallow a bitter pill. Probably more common are notions regarding medication and "being sick.

The unspoken meaning they perceive may be, "You need medications, thus you are sick. A common underlying concern sparked by the recommendation for psychotrop- ics is, "The therapist must think I can't handle things on my own — thinks I need a crutch. Morality pervades many beliefs about the taking of drugs for emotional problems. Some people erroneously assume that all psychiatric drugs are alike. They conclude that all psychotropics are "tranquilizers," that all can lead to drug addiction, and that such dependence on drugs is little different than alcoholism.

Thus, if you take drugs, you are bad or, at the very least, weak willed.

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Considering their closeness in age and early association, siblings can bond for a lifetime. Psychologists are beginning to appreciate the sibling link and its dynamic role in a child's social development. Beyond the mother-child dyad, sibling associations are now seen to determine cognitive faculties, emotional balance, self-sufficiency, and peer interaction. Clarifying the complex processes of these relationships and the benefits of parental involvement, Avidan Milevsky provides a foundational text for a growing area of study.

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Patients with congenital adrenal hyperplasia and hyperaldosteronism were excluded. Six patients with Cushing's disease diagnosed in earlier years were treated by total adrenalectomy and recently two patients underwent transsphenoidal removal of pituitary tumors.

Bilateral adrenalectomy was carried out in one patient with micronodular hyperplasia and in a second because of elevated adrenocorticotrophic hormone ACTH levels from an undefined source. Eight patients had adrenal neoplasms, including five adenomas and three carcinomas. We found no reliable criteria to differentiate before surgery between adrenal adenomas and adrenal carcinomas.

The most recognizable characteristic of malignancy was tumor size, specifically weight greater than 75 gms. Of the three patients with adrenal carcinoma, one expired 20 months after adrenalectomy and 8 months after receiving palliative partial hepatectomy for liver metastasis.

Two patients are well with normal growth and development at 11 and 20 years following adrenalectomy. With the exception of one patient who died 6 years after surgery from a glioblastoma multiforme, all patients with adrenal adenomas are well.

Eight patients underwent bilateral adrenalectomy for hypercortisolism.

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