Carl Sherman

An independent work group of 25 psychiatrists has issued the first new guidelines for the treatment of children with bipolar disorder in nearly a decade.

The consensus document arose out of a need for updated information first voiced by the Child and Adolescent Bipolar Foundation, a parent advocacy organization, said Robert Kowatch, M.D., professor of psychiatry and pediatrics at Cincinnati Children's Hospital/University of Cincinnati, who organized and chaired the project.

Bipolar management in children has changed considerably since the American Academy of Child and Adolescent Psychiatry published its 1997 Practice Parameters, but the subject remains “infused with considerable controversy, debate, and dyspepsia,” Jon McClellan, M.D., of the University of Washington, Seattle, said in his accompanying commentary (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:236-9).

Although the AACAP practice parameters are under revision, “we wanted something different in approach and a bit more independent,” Dr. Kowatch said. The goal was a “broad-based integration of what we know in the field: educational assessment and family therapy as well as medication.”

The guidelines are intended for “anyone who treats these kids, diagnostically and therapeutically”—psychologists and primary care physicians along with psychiatrists—and reflect the uncertainties surrounding the disorder, he said.

The guidelines lead clinicians through a comprehensive evaluation to differentiate manic symptoms like euphoria, grandiosity, and increase in goal-directed activity from manifestations of other disorders (notably attention-deficit hyperactivity disorder) and from normal behavior (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:213-35).

“There's a lot of controversy in the field about what these kids look like. We wanted to address some of that,” Dr. Kowatch said.

Confronting the difficulty of fitting kids into a diagnostic protocol that was designed for adults, the guidelines attempt “to make DSM-IV criteria developmentally appropriate,” he said.

The sections on treatment include two algorithms—acute manic or mixed episodes with and without psychosis—and shorter discussions of depression, comorbid disorders, and maintenance, using a standard system of evidence levels (randomized controlled trials in children to case reports) to characterize research support.

The biggest problem in “making the guidelines is that we just don't know much about treatment for these kids,” Dr. Kowatch said. “There aren't a lot of controlled data.” Besides lithium, which is approved for patients down to age 12 years, pharmacotherapy is off label, he noted.

Several large clinical trials, currently underway, should sharpen the picture, he suggested.

Robert L. Hendren, D.O., director of child and adolescent psychiatry at the University of California, Davis, said the work group “did a great job in advancing the field by defining what bipolar disorder is in children and adolescents, and what algorithms to consider in treating them,” Dr. Hendren said.

The result unavoidably reflects the limitations of the data. “This group thought carefully about what it is saying, but couldn't recommend whether to start with a mood stabilizer or an atypical antipsychotic; and if a mood stabilizer, they waffled between lithium and divalproex,” he said, “but that's the state of the art.”

He agreed with Dr. McClellan's commentary that the inclusion of brief, intense outbursts of mood and behavior dysregulation under the bipolar rubric implies a fundamental change in the definition of the illness. “There's a real controversy whether this represents bipolar I or II, or a developmental phase for some kids,” he said.

An independent work group of 25 psychiatrists has issued the first new guidelines for the treatment of children with bipolar disorder in nearly a decade.

The consensus document arose out of a need for updated information first voiced by the Child and Adolescent Bipolar Foundation, a parent advocacy organization, said Robert Kowatch, M.D., professor of psychiatry and pediatrics at Cincinnati Children's Hospital/University of Cincinnati, who organized and chaired the project.

Bipolar management in children has changed considerably since the American Academy of Child and Adolescent Psychiatry published its 1997 Practice Parameters, but the subject remains “infused with considerable controversy, debate, and dyspepsia,” Jon McClellan, M.D., of the University of Washington, Seattle, said in his accompanying commentary (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:236-9).

Although the AACAP practice parameters are under revision, “we wanted something different in approach and a bit more independent,” Dr. Kowatch said. The goal was a “broad-based integration of what we know in the field: educational assessment and family therapy as well as medication.”

The guidelines are intended for “anyone who treats these kids, diagnostically and therapeutically”—psychologists and primary care physicians along with psychiatrists—and reflect the uncertainties surrounding the disorder, he said.

The guidelines lead clinicians through a comprehensive evaluation to differentiate manic symptoms like euphoria, grandiosity, and increase in goal-directed activity from manifestations of other disorders (notably attention-deficit hyperactivity disorder) and from normal behavior (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:213-35).

“There's a lot of controversy in the field about what these kids look like. We wanted to address some of that,” Dr. Kowatch said.

Confronting the difficulty of fitting kids into a diagnostic protocol that was designed for adults, the guidelines attempt “to make DSM-IV criteria developmentally appropriate,” he said.

The sections on treatment include two algorithms—acute manic or mixed episodes with and without psychosis—and shorter discussions of depression, comorbid disorders, and maintenance, using a standard system of evidence levels (randomized controlled trials in children to case reports) to characterize research support.

The biggest problem in “making the guidelines is that we just don't know much about treatment for these kids,” Dr. Kowatch said. “There aren't a lot of controlled data.” Besides lithium, which is approved for patients down to age 12 years, pharmacotherapy is off label, he noted.

Several large clinical trials, currently underway, should sharpen the picture, he suggested.

Robert L. Hendren, D.O., director of child and adolescent psychiatry at the University of California, Davis, said the work group “did a great job in advancing the field by defining what bipolar disorder is in children and adolescents, and what algorithms to consider in treating them,” Dr. Hendren said.

The result unavoidably reflects the limitations of the data. “This group thought carefully about what it is saying, but couldn't recommend whether to start with a mood stabilizer or an atypical antipsychotic; and if a mood stabilizer, they waffled between lithium and divalproex,” he said, “but that's the state of the art.”

He agreed with Dr. McClellan's commentary that the inclusion of brief, intense outbursts of mood and behavior dysregulation under the bipolar rubric implies a fundamental change in the definition of the illness. “There's a real controversy whether this represents bipolar I or II, or a developmental phase for some kids,” he said.

An independent work group of 25 psychiatrists has issued the first new guidelines for the treatment of children with bipolar disorder in nearly a decade.

The consensus document arose out of a need for updated information first voiced by the Child and Adolescent Bipolar Foundation, a parent advocacy organization, said Robert Kowatch, M.D., professor of psychiatry and pediatrics at Cincinnati Children's Hospital/University of Cincinnati, who organized and chaired the project.

Bipolar management in children has changed considerably since the American Academy of Child and Adolescent Psychiatry published its 1997 Practice Parameters, but the subject remains “infused with considerable controversy, debate, and dyspepsia,” Jon McClellan, M.D., of the University of Washington, Seattle, said in his accompanying commentary (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:236-9).

Although the AACAP practice parameters are under revision, “we wanted something different in approach and a bit more independent,” Dr. Kowatch said. The goal was a “broad-based integration of what we know in the field: educational assessment and family therapy as well as medication.”

The guidelines are intended for “anyone who treats these kids, diagnostically and therapeutically”—psychologists and primary care physicians along with psychiatrists—and reflect the uncertainties surrounding the disorder, he said.

The guidelines lead clinicians through a comprehensive evaluation to differentiate manic symptoms like euphoria, grandiosity, and increase in goal-directed activity from manifestations of other disorders (notably attention-deficit hyperactivity disorder) and from normal behavior (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:213-35).

“There's a lot of controversy in the field about what these kids look like. We wanted to address some of that,” Dr. Kowatch said.

Confronting the difficulty of fitting kids into a diagnostic protocol that was designed for adults, the guidelines attempt “to make DSM-IV criteria developmentally appropriate,” he said.

The sections on treatment include two algorithms—acute manic or mixed episodes with and without psychosis—and shorter discussions of depression, comorbid disorders, and maintenance, using a standard system of evidence levels (randomized controlled trials in children to case reports) to characterize research support.

The biggest problem in “making the guidelines is that we just don't know much about treatment for these kids,” Dr. Kowatch said. “There aren't a lot of controlled data.” Besides lithium, which is approved for patients down to age 12 years, pharmacotherapy is off label, he noted.

Several large clinical trials, currently underway, should sharpen the picture, he suggested.

Robert L. Hendren, D.O., director of child and adolescent psychiatry at the University of California, Davis, said the work group “did a great job in advancing the field by defining what bipolar disorder is in children and adolescents, and what algorithms to consider in treating them,” Dr. Hendren said.

The result unavoidably reflects the limitations of the data. “This group thought carefully about what it is saying, but couldn't recommend whether to start with a mood stabilizer or an atypical antipsychotic; and if a mood stabilizer, they waffled between lithium and divalproex,” he said, “but that's the state of the art.”

He agreed with Dr. McClellan's commentary that the inclusion of brief, intense outbursts of mood and behavior dysregulation under the bipolar rubric implies a fundamental change in the definition of the illness. “There's a real controversy whether this represents bipolar I or II, or a developmental phase for some kids,” he said.

NEW YORK – The branding of pharmaceuticals–the creation and manipulation of product identity through such media as direct-to-consumer advertising–exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance–Prozac is a green and white capsule, while Sarafem is pink and lavender–emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social–that is, precisely not the chemical– effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness. … They are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color–a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth–not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK – The branding of pharmaceuticals–the creation and manipulation of product identity through such media as direct-to-consumer advertising–exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance–Prozac is a green and white capsule, while Sarafem is pink and lavender–emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social–that is, precisely not the chemical– effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness. … They are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color–a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth–not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK – The branding of pharmaceuticals–the creation and manipulation of product identity through such media as direct-to-consumer advertising–exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance–Prozac is a green and white capsule, while Sarafem is pink and lavender–emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social–that is, precisely not the chemical– effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness. … They are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color–a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth–not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising— exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

"The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty," said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD).

The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the "physician information" section of its Web site for Sarafem said that "fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride)," while patients were told, in their section of the Web site, that "Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac."

While both statements are technically true, "socially they produce very different meanings," Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that "they are different drugs with the same ingredient."

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that "women told us they wanted a treatment with its own identity."

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound "whose only clinical relevance is its pharmaceutical activity," he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with "the social—that is, precisely not the chemical— effects of these drugs," he said.

The companies manipulate the symbolic meanings of their products by "mobilizing images and texts," and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that "drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified." As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to "its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world." If the brand name drug is a fantasy object, "the generic drug is truth—not a rich soil for projection."

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug.

A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising— exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

"The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty," said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD).

The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the "physician information" section of its Web site for Sarafem said that "fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride)," while patients were told, in their section of the Web site, that "Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac."

While both statements are technically true, "socially they produce very different meanings," Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that "they are different drugs with the same ingredient."

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that "women told us they wanted a treatment with its own identity."

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound "whose only clinical relevance is its pharmaceutical activity," he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with "the social—that is, precisely not the chemical— effects of these drugs," he said.

The companies manipulate the symbolic meanings of their products by "mobilizing images and texts," and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that "drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified." As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to "its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world." If the brand name drug is a fantasy object, "the generic drug is truth—not a rich soil for projection."

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug.

A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising— exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

"The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty," said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD).

The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the "physician information" section of its Web site for Sarafem said that "fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride)," while patients were told, in their section of the Web site, that "Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac."

While both statements are technically true, "socially they produce very different meanings," Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that "they are different drugs with the same ingredient."

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that "women told us they wanted a treatment with its own identity."

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound "whose only clinical relevance is its pharmaceutical activity," he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with "the social—that is, precisely not the chemical— effects of these drugs," he said.

The companies manipulate the symbolic meanings of their products by "mobilizing images and texts," and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that "drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified." As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to "its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world." If the brand name drug is a fantasy object, "the generic drug is truth—not a rich soil for projection."

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug.

A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said during the meeting.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound, he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, said that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society. He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said during the meeting.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound, he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, said that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society. He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said during the meeting.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound, he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, said that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society. He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth—not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

A member of the audience cautioned against simplistically reducing branding issues to a variant of the argument that drugs are overused or misused; he suggested that the phenomenon might well be considered more generally, extending even to patients' feelings about psychoanalysis.

“We're beneficiaries of brand loyalty, too,” he said.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth—not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

A member of the audience cautioned against simplistically reducing branding issues to a variant of the argument that drugs are overused or misused; he suggested that the phenomenon might well be considered more generally, extending even to patients' feelings about psychoanalysis.

“We're beneficiaries of brand loyalty, too,” he said.

NEW YORK — The branding of pharmaceuticals—the creation and manipulation of product identity through such media as direct-to-consumer advertising—exerts a potent influence on the way patients think and feel about their medication and their illness, Nathan Greenslit said at a meeting sponsored by the American Psychoanalytic Association.

“The marketers I've interviewed routinely think that compliance needs to be reframed as a problem of brand loyalty,” said Mr. Greenslit, a cultural anthropologist and doctoral candidate in the program in science, technology, and society at Massachusetts Institute of Technology, Cambridge.

To illustrate the impact of branding, Mr. Greenslit considered the case of Sarafem, a formulation of fluoxetine first marketed by Eli Lilly to women for premenstrual dysphoric disorder (PMDD). The rights to Sarafem have since been sold to another pharmaceutical company, Warner Chilcott Inc.

When Lilly was still marketing the drug, the “physician information” section of its Web site for Sarafem said that “fluoxetine was initially developed and marketed as an antidepressant (Prozac, fluoxetine hydrochloride),” while patients were told, in their section of the Web site, that “Sarafem contains fluoxetine hydrochloride, the same active ingredient found in Prozac.”

While both statements are technically true, “socially they produce very different meanings,” Mr. Greenslit said. Physicians were informed that Sarafem and Prozac were the same drug with different packages, while the message to patients was that “they are different drugs with the same ingredient.”

A contrast in appearance—Prozac is a green and white capsule, while Sarafem is pink and lavender—emphasized the distinction, he said.

The separate branding was justified by Lilly as a response to consumer demand, Mr. Greenslit said, citing a Lilly marketing associate who noted that women don't look at their PMDD symptoms as depression, that Prozac is closely associated with depression, and that “women told us they wanted a treatment with its own identity.”

The branding phenomenon underlines the idea that a person's relationship to a drug is more complex than his or her body's relationship to a chemical compound “whose only clinical relevance is its pharmaceutical activity,” he said.

A close look at direct-to-consumer advertising suggests the extent of pharmaceutical companies' concern with “the social—that is, precisely not the chemical— effects of these drugs,” he said. The companies manipulate the symbolic meanings of their products by “mobilizing images and texts,” and take great care to avoid mistakes that would increase stigma surrounding the drug and condition for which it is prescribed (e.g., a pink Viagra).

Mitchell D. Wilson, M.D., who discussed Mr. Greenslit's presentation, suggested that “drugs as brands take on the character of objects of fantasy, with a quality of aliveness … they are personified.”

As in interpersonal relationships, processes like identification and projection can occur, said Dr. Wilson of the San Francisco Psychoanalytic Institute and Society.

He contrasted the effect of branding to “its pale, poor step cousin, the generic drug: no name, no distinctive shape or color—a nothing in the symbolic world.” If the brand name drug is a fantasy object, “the generic drug is truth—not a rich soil for projection.”

Mr. Greenslit noted that clinical trials are conducted with the generic version of a compound before it has been branded, and thus do not take into account the role that branding might play in the patient's experience of the drug. A closer look might provide insight into connections between marketing and the placebo effect, he suggested.

A member of the audience cautioned against simplistically reducing branding issues to a variant of the argument that drugs are overused or misused; he suggested that the phenomenon might well be considered more generally, extending even to patients' feelings about psychoanalysis.

“We're beneficiaries of brand loyalty, too,” he said.

NEW YORK — An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that are Food and Drug Administration-approved to treat alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking. Of 24 double-blind controlled trials, 77% found significantly less harmful drinking with the drug compared with placebo, but many found no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, said Dr. Pettinati, professor of psychiatry at the University of Pennsylvania, Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said. The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence—it's one of the most common explanations,” she said at the meeting, cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is “I forgot,” but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant. “You see the effect right away—you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol-dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%). Adherence was high: Three-fourths in the naltrexone group received all scheduled injections.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone. In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK — An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that are Food and Drug Administration-approved to treat alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking. Of 24 double-blind controlled trials, 77% found significantly less harmful drinking with the drug compared with placebo, but many found no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, said Dr. Pettinati, professor of psychiatry at the University of Pennsylvania, Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said. The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence—it's one of the most common explanations,” she said at the meeting, cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is “I forgot,” but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant. “You see the effect right away—you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol-dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%). Adherence was high: Three-fourths in the naltrexone group received all scheduled injections.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone. In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK — An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that are Food and Drug Administration-approved to treat alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking. Of 24 double-blind controlled trials, 77% found significantly less harmful drinking with the drug compared with placebo, but many found no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, said Dr. Pettinati, professor of psychiatry at the University of Pennsylvania, Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said. The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence—it's one of the most common explanations,” she said at the meeting, cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is “I forgot,” but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant. “You see the effect right away—you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol-dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%). Adherence was high: Three-fourths in the naltrexone group received all scheduled injections.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone. In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK – An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that have received approval from the Food and Drug Administration for alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking.

Of 24 double-blind controlled trials, 77% found that there was significantly less harmful drinking with the drug, compared with placebo, but many found that there was no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, according to Dr. Pettinati, who is professor of psychiatry at the University of Pennsylvania in Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said.

The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence–it's one of the most common explanations,” she pointed out at the meeting, which was cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is 'I forgot,' but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant.

“You see the effect right away–you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%).

Adherence was high: Three-fourths of patients in the naltrexone group received all scheduled injections, Dr. Pettinati said.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone.

In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK – An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that have received approval from the Food and Drug Administration for alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking.

Of 24 double-blind controlled trials, 77% found that there was significantly less harmful drinking with the drug, compared with placebo, but many found that there was no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, according to Dr. Pettinati, who is professor of psychiatry at the University of Pennsylvania in Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said.

The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence–it's one of the most common explanations,” she pointed out at the meeting, which was cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is 'I forgot,' but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant.

“You see the effect right away–you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%).

Adherence was high: Three-fourths of patients in the naltrexone group received all scheduled injections, Dr. Pettinati said.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone.

In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK – An injectable depot formulation of naltrexone, now in phase III trials, may help overcome the adherence problems that have compromised the drug's efficacy in the treatment of alcohol dependence, Helen M. Pettinati, Ph.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Naltrexone is one of three drugs that have received approval from the Food and Drug Administration for alcoholism. The compound, an opioid antagonist first used for opiate addiction, blocks reward pathways in the brain. It appears to reduce the excitement that some derive from alcohol ingestion, as well as alcohol craving.

Treatment with naltrexone appears less consistent with total abstinence than with reduction in excessive drinking.

Of 24 double-blind controlled trials, 77% found that there was significantly less harmful drinking with the drug, compared with placebo, but many found that there was no difference in drinking days or other measures of abstinence.

Clinically, compliance difficulties have limited the utility of naltrexone, according to Dr. Pettinati, who is professor of psychiatry at the University of Pennsylvania in Philadelphia.

In one study, rates of relapse to heavy drinking were significantly lower among 60 naltrexone patients than among 44 placebo patients who attended 80% of clinic visits (10% vs. 38%). But there was no difference in relapse rate between 50 patients who were nonadherent to placebo and 42 who failed to follow the naltrexone regimen: 40% vs. 42%, respectively.

Attention to adherence should be a routine, proactive part of naltrexone treatment, Dr. Pettinati said.

The actual use of the medication may be monitored with blister packs or diaries. “If there's a poor response to treatment, ask about adherence–it's one of the most common explanations,” she pointed out at the meeting, which was cosponsored by the New York Academy of Medicine.

Reasons for nonadherence should be explored and strategies devised to overcome problems. “The most common reason patients give for not taking the medication is 'I forgot,' but usually it's because they feel they are getting better and want to go out drinking,” she said.

The depot formulation of naltrexone should provide an alternative to tablets that will reduce adherence difficulties. The intramuscular preparation lasts for 30 days. In a 24-week study involving 624 people, those receiving 380 mg of naltrexone monthly had significantly (25%) fewer days of heavy drinking per month than did those receiving placebo. Participants on a lower dosage (190 mg) of the drug had 17% fewer drinking days, which was not significant.

“You see the effect right away–you don't have to wait 6 months,” Dr. Pettinati said.

Contrary to some concerns, patients appeared to have no difficulty adhering to the regimen: Seventy-four percent took at least four of the six injections.

In another study of 315 alcohol dependent persons, those taking a somewhat lower dose (150 mg/mo) of depot naltrexone were significantly more likely to remain abstinent than was a placebo group during a 12-week study (18% vs. 10%).

Adherence was high: Three-fourths of patients in the naltrexone group received all scheduled injections, Dr. Pettinati said.

Other recent research suggests that variations in a μ-opiate receptor gene may account for differences in response to naltrexone.

In one study, those with one or two copies of the allele Asp40 had significantly lower relapse rates and a longer time to heavy drinking, when treated with naltrexone, than did those who were homozygous for the Asn40 allele, Dr. Pettinati said.

NEW YORK — Herb-using individuals who are at risk of bleeding should be advised to use caution, despite uncertainty about the actual degree of risk that may be involved, Adrian Fugh-Berman, M.D., said at a meeting on botanical medicine sponsored by Columbia University and the University of Arizona.

"Actual, theoretical, and fanciful herbal adverse events and interactions infest the medical literature," said Dr. Fugh-Berman of Georgetown University, Washington.

Given the level of uncertainty, it is prudent to check international normalized ratio (INR) of anticoagulated patients 7–14 days after starting any herbal, dietary supplement, or weight-loss regimen. By the same token, all herbs and supplements should be discontinued 2 weeks before surgery, she said.

Many herbs contain coumarins, most of which are benign. Some inhibit platelet aggregation in vitro, but few have been associated with actual bleeding episodes.

In one study, a 10-g dose of ginger decreased platelet aggregation 4 hours later, and a case was reported in which a 76-year-old woman developed nosebleeds and showed changes in INR after eating dried ginger and drinking tea made from it for several weeks. But three clinical studies found that up to 4 g of fresh ginger daily had no effect on bleeding.

Garlic oil has been shown to decrease platelet aggregation for up to 6 hours, and two cases of excessive postsurgical bleeding have been reported in which patients had consumed garlic-laden meals the night before.

"Tell patients not to consume meals heavy in garlic within a few days of surgery," Dr. Fugh-Berman advised.

Ginkgolide B, a component of Ginkgo biloba, is a known platelet aggregation factor antagonist, and the herb, alone or with analgesics, has been associated with intracranial bleeding events.

Clinical studies, however, found that one standardized ginkgo preparation (EGb761) had no effect on hemostasis, coagulation, or fibrinolysis in healthy men, and another (Bio-Biloba) did not change INR in patients who had been stabilized on warfarin.

NEW YORK — Herb-using individuals who are at risk of bleeding should be advised to use caution, despite uncertainty about the actual degree of risk that may be involved, Adrian Fugh-Berman, M.D., said at a meeting on botanical medicine sponsored by Columbia University and the University of Arizona.

"Actual, theoretical, and fanciful herbal adverse events and interactions infest the medical literature," said Dr. Fugh-Berman of Georgetown University, Washington.

Given the level of uncertainty, it is prudent to check international normalized ratio (INR) of anticoagulated patients 7–14 days after starting any herbal, dietary supplement, or weight-loss regimen. By the same token, all herbs and supplements should be discontinued 2 weeks before surgery, she said.

Many herbs contain coumarins, most of which are benign. Some inhibit platelet aggregation in vitro, but few have been associated with actual bleeding episodes.

In one study, a 10-g dose of ginger decreased platelet aggregation 4 hours later, and a case was reported in which a 76-year-old woman developed nosebleeds and showed changes in INR after eating dried ginger and drinking tea made from it for several weeks. But three clinical studies found that up to 4 g of fresh ginger daily had no effect on bleeding.

Garlic oil has been shown to decrease platelet aggregation for up to 6 hours, and two cases of excessive postsurgical bleeding have been reported in which patients had consumed garlic-laden meals the night before.

"Tell patients not to consume meals heavy in garlic within a few days of surgery," Dr. Fugh-Berman advised.

Ginkgolide B, a component of Ginkgo biloba, is a known platelet aggregation factor antagonist, and the herb, alone or with analgesics, has been associated with intracranial bleeding events.

Clinical studies, however, found that one standardized ginkgo preparation (EGb761) had no effect on hemostasis, coagulation, or fibrinolysis in healthy men, and another (Bio-Biloba) did not change INR in patients who had been stabilized on warfarin.

NEW YORK — Herb-using individuals who are at risk of bleeding should be advised to use caution, despite uncertainty about the actual degree of risk that may be involved, Adrian Fugh-Berman, M.D., said at a meeting on botanical medicine sponsored by Columbia University and the University of Arizona.

"Actual, theoretical, and fanciful herbal adverse events and interactions infest the medical literature," said Dr. Fugh-Berman of Georgetown University, Washington.

Given the level of uncertainty, it is prudent to check international normalized ratio (INR) of anticoagulated patients 7–14 days after starting any herbal, dietary supplement, or weight-loss regimen. By the same token, all herbs and supplements should be discontinued 2 weeks before surgery, she said.

Many herbs contain coumarins, most of which are benign. Some inhibit platelet aggregation in vitro, but few have been associated with actual bleeding episodes.

In one study, a 10-g dose of ginger decreased platelet aggregation 4 hours later, and a case was reported in which a 76-year-old woman developed nosebleeds and showed changes in INR after eating dried ginger and drinking tea made from it for several weeks. But three clinical studies found that up to 4 g of fresh ginger daily had no effect on bleeding.

Garlic oil has been shown to decrease platelet aggregation for up to 6 hours, and two cases of excessive postsurgical bleeding have been reported in which patients had consumed garlic-laden meals the night before.

"Tell patients not to consume meals heavy in garlic within a few days of surgery," Dr. Fugh-Berman advised.

Ginkgolide B, a component of Ginkgo biloba, is a known platelet aggregation factor antagonist, and the herb, alone or with analgesics, has been associated with intracranial bleeding events.

Clinical studies, however, found that one standardized ginkgo preparation (EGb761) had no effect on hemostasis, coagulation, or fibrinolysis in healthy men, and another (Bio-Biloba) did not change INR in patients who had been stabilized on warfarin.

NEW YORK — With a fuller understanding of the neurobiology of tobacco dependence, potential therapeutic targets have emerged that suggest novel treatments for this devastating health problem, Robert Anthenelli, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Of particular promise are drugs that target nicotinic receptor subtypes, endocannabinoid antagonists, and selective MAO inhibitors, said Dr. Anthenelli, director of the substance dependence program at the Veterans Affairs Medical Center in Cincinnati.

Tobacco is more likely than alcohol or cocaine to produce dependence in users and is responsible for enormous amounts of mortality and morbidity worldwide, but there are only two approved drug treatment modalities—nicotine replacement and bupropion—and neither is terribly effective, he said.

Neurobiologic research has shown that the acetylcholine system plays a key role in nicotine response and dependence. Nicotinic receptors, which bind acetylcholine, are present on almost all neurons and mediate attention, arousal, and cognition.

Diversity of subunit composition allows nicotinic receptors to be involved in a number of different processes. It appears that two subtypes, α4β2, which predominates in the brain, and α7, are key players in tobacco dependence, he explained.

Initially, nicotine stimulates these receptors (and through them, the firing of dopaminergic neurons), producing tobacco's desired effects. Over time, though, exposure pushes the receptors into a desensitized state that promotes tolerance. Their consequent upregulation contributes to withdrawal symptoms that make smoking cessation difficult, Dr. Anthenelli said at the meeting, which was cosponsored by the New York Academy of Medicine.

Partial agonists to the α4β2 nicotinic receptor are currently under development. In the presence of nicotine, these drugs work like antagonists, blocking the drug's reinforcing effect; in its absence, they ameliorate withdrawal.

In a phase IIa study, almost half of smokers taking one such drug, varenicline, successfully quit after 7 weeks, compared with 16% taking placebo and one-third taking bupropion. In this and other studies, the drug's side effect profile appeared to be benign, Dr. Anthenelli said.

Other compounds in this class also are under investigation, he said.

Another intriguing target for novel interventions is the endocannabinoid system, which acts in the mesolimbic area of the brain and regulates appetite and other functions. Nicotine stimulates the release of endocannabinoids in the limbic forebrain.

Rimonabant, the first compound developed to modulate this system, works through its influence on one type of receptor (cannabinoid-1). It has aroused great interest for its effects on weight and lipid metabolism but appears to be promising as an aid to smoking cessation as well, Dr. Anthenelli said.

In a phase III trial, rimonabant (20 mg/day) achieved significantly greater abstinence rates than did placebo, as measured during the last 4 weeks of a 10-week trial: 27.6% vs. 15.6% by intent-to-treat analysis, 36% vs. 20% among completers. A lower dosage of the drug (5 mg/day) was no more effective than placebo.

It is particularly encouraging, since weight gain is an important obstacle for many who try to quit smoking, that weight changed little for those on the drug: a mean gain of 0.6 kg, compared with 7.3 kg on placebo, Dr. Anthenelli said.

Selective MAO inhibitors also are being investigated for this application. Cigarette smoke inhibits MAO activity, possibly through components other than nicotine, and the selective MAO inhibitor selegiline reduced craving and smoking in a laboratory study. In a controlled trial, 25% of patients who added selegiline to nicotine replacement achieved abstinence after a year, compared with 11% of those who used nicotine replacement and placebo.

NEW YORK — With a fuller understanding of the neurobiology of tobacco dependence, potential therapeutic targets have emerged that suggest novel treatments for this devastating health problem, Robert Anthenelli, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Of particular promise are drugs that target nicotinic receptor subtypes, endocannabinoid antagonists, and selective MAO inhibitors, said Dr. Anthenelli, director of the substance dependence program at the Veterans Affairs Medical Center in Cincinnati.

Tobacco is more likely than alcohol or cocaine to produce dependence in users and is responsible for enormous amounts of mortality and morbidity worldwide, but there are only two approved drug treatment modalities—nicotine replacement and bupropion—and neither is terribly effective, he said.

Neurobiologic research has shown that the acetylcholine system plays a key role in nicotine response and dependence. Nicotinic receptors, which bind acetylcholine, are present on almost all neurons and mediate attention, arousal, and cognition.

Diversity of subunit composition allows nicotinic receptors to be involved in a number of different processes. It appears that two subtypes, α4β2, which predominates in the brain, and α7, are key players in tobacco dependence, he explained.

Initially, nicotine stimulates these receptors (and through them, the firing of dopaminergic neurons), producing tobacco's desired effects. Over time, though, exposure pushes the receptors into a desensitized state that promotes tolerance. Their consequent upregulation contributes to withdrawal symptoms that make smoking cessation difficult, Dr. Anthenelli said at the meeting, which was cosponsored by the New York Academy of Medicine.

Partial agonists to the α4β2 nicotinic receptor are currently under development. In the presence of nicotine, these drugs work like antagonists, blocking the drug's reinforcing effect; in its absence, they ameliorate withdrawal.

In a phase IIa study, almost half of smokers taking one such drug, varenicline, successfully quit after 7 weeks, compared with 16% taking placebo and one-third taking bupropion. In this and other studies, the drug's side effect profile appeared to be benign, Dr. Anthenelli said.

Other compounds in this class also are under investigation, he said.

Another intriguing target for novel interventions is the endocannabinoid system, which acts in the mesolimbic area of the brain and regulates appetite and other functions. Nicotine stimulates the release of endocannabinoids in the limbic forebrain.

Rimonabant, the first compound developed to modulate this system, works through its influence on one type of receptor (cannabinoid-1). It has aroused great interest for its effects on weight and lipid metabolism but appears to be promising as an aid to smoking cessation as well, Dr. Anthenelli said.

In a phase III trial, rimonabant (20 mg/day) achieved significantly greater abstinence rates than did placebo, as measured during the last 4 weeks of a 10-week trial: 27.6% vs. 15.6% by intent-to-treat analysis, 36% vs. 20% among completers. A lower dosage of the drug (5 mg/day) was no more effective than placebo.

It is particularly encouraging, since weight gain is an important obstacle for many who try to quit smoking, that weight changed little for those on the drug: a mean gain of 0.6 kg, compared with 7.3 kg on placebo, Dr. Anthenelli said.

Selective MAO inhibitors also are being investigated for this application. Cigarette smoke inhibits MAO activity, possibly through components other than nicotine, and the selective MAO inhibitor selegiline reduced craving and smoking in a laboratory study. In a controlled trial, 25% of patients who added selegiline to nicotine replacement achieved abstinence after a year, compared with 11% of those who used nicotine replacement and placebo.

NEW YORK — With a fuller understanding of the neurobiology of tobacco dependence, potential therapeutic targets have emerged that suggest novel treatments for this devastating health problem, Robert Anthenelli, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

Of particular promise are drugs that target nicotinic receptor subtypes, endocannabinoid antagonists, and selective MAO inhibitors, said Dr. Anthenelli, director of the substance dependence program at the Veterans Affairs Medical Center in Cincinnati.

Tobacco is more likely than alcohol or cocaine to produce dependence in users and is responsible for enormous amounts of mortality and morbidity worldwide, but there are only two approved drug treatment modalities—nicotine replacement and bupropion—and neither is terribly effective, he said.

Neurobiologic research has shown that the acetylcholine system plays a key role in nicotine response and dependence. Nicotinic receptors, which bind acetylcholine, are present on almost all neurons and mediate attention, arousal, and cognition.

Diversity of subunit composition allows nicotinic receptors to be involved in a number of different processes. It appears that two subtypes, α4β2, which predominates in the brain, and α7, are key players in tobacco dependence, he explained.

Initially, nicotine stimulates these receptors (and through them, the firing of dopaminergic neurons), producing tobacco's desired effects. Over time, though, exposure pushes the receptors into a desensitized state that promotes tolerance. Their consequent upregulation contributes to withdrawal symptoms that make smoking cessation difficult, Dr. Anthenelli said at the meeting, which was cosponsored by the New York Academy of Medicine.

Partial agonists to the α4β2 nicotinic receptor are currently under development. In the presence of nicotine, these drugs work like antagonists, blocking the drug's reinforcing effect; in its absence, they ameliorate withdrawal.

In a phase IIa study, almost half of smokers taking one such drug, varenicline, successfully quit after 7 weeks, compared with 16% taking placebo and one-third taking bupropion. In this and other studies, the drug's side effect profile appeared to be benign, Dr. Anthenelli said.

Other compounds in this class also are under investigation, he said.

Another intriguing target for novel interventions is the endocannabinoid system, which acts in the mesolimbic area of the brain and regulates appetite and other functions. Nicotine stimulates the release of endocannabinoids in the limbic forebrain.

Rimonabant, the first compound developed to modulate this system, works through its influence on one type of receptor (cannabinoid-1). It has aroused great interest for its effects on weight and lipid metabolism but appears to be promising as an aid to smoking cessation as well, Dr. Anthenelli said.

In a phase III trial, rimonabant (20 mg/day) achieved significantly greater abstinence rates than did placebo, as measured during the last 4 weeks of a 10-week trial: 27.6% vs. 15.6% by intent-to-treat analysis, 36% vs. 20% among completers. A lower dosage of the drug (5 mg/day) was no more effective than placebo.

It is particularly encouraging, since weight gain is an important obstacle for many who try to quit smoking, that weight changed little for those on the drug: a mean gain of 0.6 kg, compared with 7.3 kg on placebo, Dr. Anthenelli said.

Selective MAO inhibitors also are being investigated for this application. Cigarette smoke inhibits MAO activity, possibly through components other than nicotine, and the selective MAO inhibitor selegiline reduced craving and smoking in a laboratory study. In a controlled trial, 25% of patients who added selegiline to nicotine replacement achieved abstinence after a year, compared with 11% of those who used nicotine replacement and placebo.

NEW YORK — Disulfiram, a drug that has long been used for alcohol dependence, appears promising for the treatment of cocaine addiction, Thomas Kosten, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

A variety of medications, most developed for other indications, may ameliorate problems associated with cocaine and other stimulants by addressing diverse points of the complex neurobiological processes involved, said Dr. Kosten, professor of psychiatry at Yale University, New Haven.

Increased release of dopamine, particularly in the nucleus accumbens, is the signature of drug reward; addiction, however, induces a hypodopaminergic state by downregulating dopamine receptors. Treatment that addresses this neural substrate should reverse the stimulant-induced dopamine deficiency.

D2 receptor agonists, such as bromocriptine, have proved ineffective in this regard, but indirect dopamine agonists also seem promising. Most prominent is disulfiram, which inhibits the conversion of dopamine to norepinephrine. The compound has been shown to attenuate the craving induced by administration of cocaine and to reduce withdrawal.

Another mechanism by which disulfiram facilitates reduction in cocaine use appears to be tied to the acceleration and accentuation of the nervousness and dysphoria that often follow ingestion of the drug, Dr. Kosten said at the meeting, cosponsored by the New York Academy of Medicine.

A metaanalysis of a series of studies involving 337 individuals given disulfiram or one of several control medications (naltrexone, buprenorphine, or methadone, for example) found that drug-free urines were significantly more frequent in those on disulfiram than controls (55% vs. 40%).

Another study suggested a genetic explanation for the superior efficacy of disulfiram in some patients but not others. In half of the subjects, the drug did not increase nervousness and paranoia after cocaine ingestion, which could be attributed to differences in levels of dopamine β-hydroxylase (DβH), the target of disulfiram: Low endogenous levels of DβH should predict the cocaine-induced dysphoria that is linked to treatment response.

In fact, disulfiram was associated with significantly more cocaine-free urines than placebo among people with at least one copy of the allele linked to low DβH but not among those who lacked that gene, Dr. Kosten said.

Amantadine, an indirect dopamine agonist that facilitates release of the neurotransmitter, has been shown to be more effective than placebo—but only in people who suffer severe withdrawal symptoms.

The same pattern has been seen with adrenergic antagonists: Propanolol was superior to placebo in reducing cocaine use and increasing treatment retention in patients with high but not low withdrawal severity, he said.

The GABA system is also dysregulated in cocaine dependence; a two-thirds reduction in GABA tone compromises the inhibitory function of this neurotransmitter system. The GABA agonist baclofen was significantly superior to placebo in achieving abstinence from cocaine, as indicated by cocaine-free urines, and tiagibine has also looked promising in controlled trials. Although there is less evidence, other drugs with similar mechanisms of activity (gabapentin, vigabatrin, topiramate) may be useful as well.

Modafinil, a glutamate agonist, has been shown superior to placebo in reducing cocaine use, possibly through its enhancement of the ability to stop unwanted behaviors and to learn relapse-prevention skills, Dr. Kosten said.

A vaccine called TA-CD, under development by Xenova Group PLC, generates antibodies that prevent cocaine from crossing the blood-brain barrier. In a study of 11 patients, a five-dose series of vaccinations was associated with reduced cocaine use for 1 year, without major adverse effects, he said.

NEW YORK — Disulfiram, a drug that has long been used for alcohol dependence, appears promising for the treatment of cocaine addiction, Thomas Kosten, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

A variety of medications, most developed for other indications, may ameliorate problems associated with cocaine and other stimulants by addressing diverse points of the complex neurobiological processes involved, said Dr. Kosten, professor of psychiatry at Yale University, New Haven.

Increased release of dopamine, particularly in the nucleus accumbens, is the signature of drug reward; addiction, however, induces a hypodopaminergic state by downregulating dopamine receptors. Treatment that addresses this neural substrate should reverse the stimulant-induced dopamine deficiency.

D2 receptor agonists, such as bromocriptine, have proved ineffective in this regard, but indirect dopamine agonists also seem promising. Most prominent is disulfiram, which inhibits the conversion of dopamine to norepinephrine. The compound has been shown to attenuate the craving induced by administration of cocaine and to reduce withdrawal.

Another mechanism by which disulfiram facilitates reduction in cocaine use appears to be tied to the acceleration and accentuation of the nervousness and dysphoria that often follow ingestion of the drug, Dr. Kosten said at the meeting, cosponsored by the New York Academy of Medicine.

A metaanalysis of a series of studies involving 337 individuals given disulfiram or one of several control medications (naltrexone, buprenorphine, or methadone, for example) found that drug-free urines were significantly more frequent in those on disulfiram than controls (55% vs. 40%).

Another study suggested a genetic explanation for the superior efficacy of disulfiram in some patients but not others. In half of the subjects, the drug did not increase nervousness and paranoia after cocaine ingestion, which could be attributed to differences in levels of dopamine β-hydroxylase (DβH), the target of disulfiram: Low endogenous levels of DβH should predict the cocaine-induced dysphoria that is linked to treatment response.

In fact, disulfiram was associated with significantly more cocaine-free urines than placebo among people with at least one copy of the allele linked to low DβH but not among those who lacked that gene, Dr. Kosten said.

Amantadine, an indirect dopamine agonist that facilitates release of the neurotransmitter, has been shown to be more effective than placebo—but only in people who suffer severe withdrawal symptoms.

The same pattern has been seen with adrenergic antagonists: Propanolol was superior to placebo in reducing cocaine use and increasing treatment retention in patients with high but not low withdrawal severity, he said.

The GABA system is also dysregulated in cocaine dependence; a two-thirds reduction in GABA tone compromises the inhibitory function of this neurotransmitter system. The GABA agonist baclofen was significantly superior to placebo in achieving abstinence from cocaine, as indicated by cocaine-free urines, and tiagibine has also looked promising in controlled trials. Although there is less evidence, other drugs with similar mechanisms of activity (gabapentin, vigabatrin, topiramate) may be useful as well.

Modafinil, a glutamate agonist, has been shown superior to placebo in reducing cocaine use, possibly through its enhancement of the ability to stop unwanted behaviors and to learn relapse-prevention skills, Dr. Kosten said.

A vaccine called TA-CD, under development by Xenova Group PLC, generates antibodies that prevent cocaine from crossing the blood-brain barrier. In a study of 11 patients, a five-dose series of vaccinations was associated with reduced cocaine use for 1 year, without major adverse effects, he said.

NEW YORK — Disulfiram, a drug that has long been used for alcohol dependence, appears promising for the treatment of cocaine addiction, Thomas Kosten, M.D., said at the annual conference of the Association for Research in Nervous and Mental Disease.

A variety of medications, most developed for other indications, may ameliorate problems associated with cocaine and other stimulants by addressing diverse points of the complex neurobiological processes involved, said Dr. Kosten, professor of psychiatry at Yale University, New Haven.

Increased release of dopamine, particularly in the nucleus accumbens, is the signature of drug reward; addiction, however, induces a hypodopaminergic state by downregulating dopamine receptors. Treatment that addresses this neural substrate should reverse the stimulant-induced dopamine deficiency.

D2 receptor agonists, such as bromocriptine, have proved ineffective in this regard, but indirect dopamine agonists also seem promising. Most prominent is disulfiram, which inhibits the conversion of dopamine to norepinephrine. The compound has been shown to attenuate the craving induced by administration of cocaine and to reduce withdrawal.

Another mechanism by which disulfiram facilitates reduction in cocaine use appears to be tied to the acceleration and accentuation of the nervousness and dysphoria that often follow ingestion of the drug, Dr. Kosten said at the meeting, cosponsored by the New York Academy of Medicine.

A metaanalysis of a series of studies involving 337 individuals given disulfiram or one of several control medications (naltrexone, buprenorphine, or methadone, for example) found that drug-free urines were significantly more frequent in those on disulfiram than controls (55% vs. 40%).

Another study suggested a genetic explanation for the superior efficacy of disulfiram in some patients but not others. In half of the subjects, the drug did not increase nervousness and paranoia after cocaine ingestion, which could be attributed to differences in levels of dopamine β-hydroxylase (DβH), the target of disulfiram: Low endogenous levels of DβH should predict the cocaine-induced dysphoria that is linked to treatment response.

In fact, disulfiram was associated with significantly more cocaine-free urines than placebo among people with at least one copy of the allele linked to low DβH but not among those who lacked that gene, Dr. Kosten said.

Amantadine, an indirect dopamine agonist that facilitates release of the neurotransmitter, has been shown to be more effective than placebo—but only in people who suffer severe withdrawal symptoms.

The same pattern has been seen with adrenergic antagonists: Propanolol was superior to placebo in reducing cocaine use and increasing treatment retention in patients with high but not low withdrawal severity, he said.

The GABA system is also dysregulated in cocaine dependence; a two-thirds reduction in GABA tone compromises the inhibitory function of this neurotransmitter system. The GABA agonist baclofen was significantly superior to placebo in achieving abstinence from cocaine, as indicated by cocaine-free urines, and tiagibine has also looked promising in controlled trials. Although there is less evidence, other drugs with similar mechanisms of activity (gabapentin, vigabatrin, topiramate) may be useful as well.

Modafinil, a glutamate agonist, has been shown superior to placebo in reducing cocaine use, possibly through its enhancement of the ability to stop unwanted behaviors and to learn relapse-prevention skills, Dr. Kosten said.

A vaccine called TA-CD, under development by Xenova Group PLC, generates antibodies that prevent cocaine from crossing the blood-brain barrier. In a study of 11 patients, a five-dose series of vaccinations was associated with reduced cocaine use for 1 year, without major adverse effects, he said.