Lessons from Secretin / APA: Protect Research Subjects / Ritvo Credited

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" Healing Autism: No Finer a Cause on the Planet "

____________________________________________________________

Lessons from Secretin / APA: Protect Research Subjects / Ritvo Credited

- Medical editorials compiled by Ron Sleith.

Friday, December 10, 1999

[From the current New England Journal of Medicine, December 9, 1999,

Vol. 341, No. 24.]

In this issue of the Journal, Sandler and colleagues report the

negative results of a double-blind, placebo-controlled trial of a single

intravenous dose of synthetic human secretin in children with autism or

pervasive developmental disorder. (1) Autistic disorder is a serious

neuropsychiatric disorder with onset in the first years of life that is

characterized by delayed and deviant social and communication skills,

associated with various forms of unusual behavior (e.g., repetitive behavior

and unusual responses to the environment). (2) The term pervasive

developmental disorder not otherwise specified refers to a condition with

symptoms suggestive of autism but that does not meet the full criteria for

autism. (2)

In the years immediately after the first description of autism in

1943, (3) there was speculation that the condition might be a form of

schizophrenia, that it was more frequent in families with higher

socioeconomic status, and that it was not associated with other medical

conditions. Subsequent research has clarified that autism and related

conditions are distinctive disorders, are seen in all social classes, and

are strongly associated with some medical conditions, notably seizure

disorder, for which persons with autism are at increased risk. (4,5) Recent

work has strongly implicated genetic factors in causing the disease; it

appears that several genes are probably involved, and several promising

leads have been identified. (6)

Studies of treatments for autism and related conditions support the

importance of structured behavioral and educational intervention. (7)

Although no pharmacologic agent has proved curative, the treatment of

specific symptoms -- for example, with neuroleptic drugs -- can greatly aid

the child's ability to be helped by such programs. (8) Despite better

detection and improved services, autism is a major burden for children and

their families. It affects 1 in approximately 2000 children (2) and is

associated with some degree of mental retardation in about 75 percent of

cases. In slightly less than half of cases, affected persons never develop

communicative speech. (2) Understandably, parents often feel overwhelmed and

devastated by this diagnosis.

As noted by Sandler et al., (1) given the absence of a " cure, " it is

not surprising that a great number of treatments have been proposed; new

treatments, often accompanied by extravagant claims that they are

responsible for marked improvement or cure, are reported regularly, although

usually with minimal or inadequate data. In the case of secretin, the

impetus for interest in this drug was the reports in the broadcast and print

media about a young child with autism who improved dramatically after

receiving this gastrointestinal peptide during a study of pancreatic

function and the report of a small, uncontrolled case series. (9) The

widespread media attention and reports of dramatic improvement and cure led

many parents to seek secretin treatment for their children, and the ensuing

frenzy led to a black market for the drug. The interest in secretin was

remarkable, because it occurred in the absence of substantive data on its

potential benefit or safety; secretin had been approved by the Food and Drug

Administration only for single-dose use in the diagnosis of certain

gastrointestinal disorders. The safety of repeated administration of

secretin, which in its original form was derived from pigs, was unclear, and

the potential for sensitization after an initial infusion was a concern.

Sandler et al. found no significant improvement in various outcome

measures after a single infusion of secretin, as compared with placebo. In

addition, they note that in both the secretin group and the placebo group

there was a significant decrease in the severity of symptoms over time

(i.e., as a result of the nonspecific but important effects of being

involved in research). (10) None of the children treated with secretin had

treatment-limiting adverse effects in this study, nor did there seem to be a

delayed beneficial effect of the secretin infusion. The authors also note

the interest of many parents in continuing the use of the drug in their

children, even after the families obtained the results of this study. The

authors rightly note the limitations of their study. It will, of course,

need replication and extension, although the emerging results from other

trials of secretin for the treatment of autism appear to be similar. (11)

Lessons to be learned from the secretin phenomenon relate to the

relation between medicine and the news media, as well as to the nature and

treatment of autism. The extensive media attention when substantive

supporting data were absent was clearly premature and unfortunate. Parents

scrambled to obtain this " cure " for their children in the absence of data on

safety and efficacy -- aided, in some cases, by well-meaning, if not

well-informed, health care professionals. What makes an interesting

television program may not, of course, be the same as what makes good

science.

Although important findings do sometimes emerge unexpectedly and

dramatically, most of the time scientific progress is made slowly and

incrementally, as investigators replicate and extend results of previous

work. In autism, the progress in clarifying the role of genetic factors is

one such example. (12) Methodical and painstaking work, however, may not be

particularly newsworthy. Will the media devote as much attention and energy

to publicizing the negative results reported by Sandler and colleagues as to

the apparent initial success of secretin? From a policy perspective,

improved communication between journalists and investigators in the attempt

to provide accurate and honest information to parents is an important but as

yet often unachieved goal.

Given the seriousness of autism, the willingness of parents to pursue

unproven or emerging treatments is understandable. Treatments that have been

considered over the years include lysergic acid diethylamide, high-dose

glucocorticoids, psychosurgery, and injections of sheep-brain extract.

Clearly, it is important that parents know that some interventions have been

proved to be effective and helpful; such treatments should not be lightly

abandoned. Examples include intensive special education and attention to the

child's behavior to improve communication, speech, and other skills. The

attempt to educate professionals by developing guidelines for the diagnosis

and treatment of autism is welcome in this regard. (8,13) Unfortunately,

claims may be made on the basis of uncontrolled, single-case reports with

all the attendant problems (e.g., ambiguities regarding diagnosis and the

nature of the treatment and the fact that some children improve without

intervention). Pursuing unproven treatments risks depleting the financial

and psychosocial resources of families. (14,15) It is important that

physicians help families make informed decisions about treatment for autism.

The nonspecific gains in behavioral and developmental functioning that

can be realized as a result of being involved in research deserve particular

mention. These gains highlight the importance of controlled research, as

well as the potential of systematic attention in improving the lives of

people with autism. (10)

Fred R. Volkmar, M.D. Yale University School of Medicine New Haven,

CT 06520

[Respond, if you please, to FEAT@... ]

* * *

APA Response to Congressional Concerns

[Dr. Appelbaum, issued a statement in response to U.S. House of

Representatives hearing on, " Do Current Federal Regulations Adequately

Protect People Who Participate in Medical Research? " ]

Dr. Appelbaum, Vice President of the American Psychiatric

Association (APA) and Secretary of its Ethics Appeals Board, issued the

following statement in response to U.S. House of Representatives Committee

on Government Reform Subcommittee hearing on, " Do Current Federal

Regulations Adequately Protect People Who Participate in Medical Research? "

" My research over the last two decades has taught me that if we are to

master the diseases that affect the brain, we must have the assistance of

persons who unfortunately suffer from mental disorders. However the

interests of the participants in the research project come first. If

research cannot be performed without violating the rights of participants,

it should not take place.

Effective research is the key to more effective treatment of these

disorders and to reduction of the suffering they cause. The introduction of

the first effective treatments for schizophrenia and other psychotic

disorders in the 1950s permitted, for the first time in history, the

long-term treatment of persons with these disorders in the community, rather

than in institutions.

The American Psychiatric Association endorses as its starting point in

addressing the complexities of this area the dual importance of three key

principles:

-- Minimize the risk to those persons who volunteer to participate in

research studies

-- Maximize participants' knowledge of what their involvement will

entail

-- Enforce safeguards required for permitting persons who lack

decision-making capacities to be entered into research projects.

Lastly, questions have been raised about the appropriateness of

studies in medicine, including mental health research, involving

discontinuation of medication. Safeguards and protections for patients are

essential. Patients should be told the possible consequences of stopping

medication and they must provide competent, informed consent and understand

the criteria for reinitiating of treatment. Medication discontinuation

studies have played and will continue to play a critical role in developing

many new medications that can transform and save thousands of patients'

lives. "

* * *

Ritvo First Reported Chromosome 13 and Recessive Form of Autism

To set the record straight -- I'm pleased and proud to let you know

that my husband, Ritvo, MD Professor Emeritus, UCLA medical school,

established the UCLA Registry for the Genetic Studies of Autism in 1980,

despite a paucity of funding (autism was a little recognized, " orphan

disease " twenty years ago). He set out to discover if genetic factors could

cause autism.

He traveled tens of thousands of miles through out the US and Europe

to personally diagnose and obtain blood samples from multiple incidence

families (doing all this, I might add, while he was suffering from

degenerative heart disease which lead to his recently receiving a heart

transplant).

Among the main published findings based on the UCLA Registry for

Genetic Studies are 1) chromosome 13 was twice identified as a candidate

gene. First via gene mapping 1985, and more specifically via studying a

multi-incidence family with autism, retinoblastoma, and reduced esterase

activity. 2) evidence for autosomal recessive inheritance of autism was

found in 46 families with multiple incidences of autism 3) in 21 of 22 sets

of identical twins (95% ) both had autism whereas only 4 of 17 (24%) non

identical twin pairs both had autism (this fits with a recessive model of

inheritance in these families) in the general population 4) the chances of

having a second autistic child if you already have one increases to

approximately 8 percent.

[Mrs. Ritvo]

____________________________________________________________

editor: Lenny Schafer schafer@... | * Not FEAT

eastern editor: , PhD CIJOHN@...

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[Guest guest]

Lessons from Secretin / APA: Protect Research Subjects /

Ritvo Credited

From: " FEAT " <feat@...>

FEAT DAILY ONLINE NEWSLETTER http://www.feat.org

Letters Editor: FEAT@... Archive: http://www.feat.org/listarchive/

M.I.N.D.*: http://mindinstitute.ucdmc.ucdavis.edu

" Healing Autism: No Finer a Cause on the Planet "

____________________________________________________________

Lessons from Secretin / APA: Protect Research Subjects / Ritvo Credited

- Medical editorials compiled by Ron Sleith.

Friday, December 10, 1999

[From the current New England Journal of Medicine, December 9, 1999,

Vol. 341, No. 24.]

In this issue of the Journal, Sandler and colleagues report the

negative results of a double-blind, placebo-controlled trial of a single

intravenous dose of synthetic human secretin in children with autism or

pervasive developmental disorder. (1) Autistic disorder is a serious

neuropsychiatric disorder with onset in the first years of life that is

characterized by delayed and deviant social and communication skills,

associated with various forms of unusual behavior (e.g., repetitive behavior

and unusual responses to the environment). (2) The term pervasive

developmental disorder not otherwise specified refers to a condition with

symptoms suggestive of autism but that does not meet the full criteria for

autism. (2)

In the years immediately after the first description of autism in

1943, (3) there was speculation that the condition might be a form of

schizophrenia, that it was more frequent in families with higher

socioeconomic status, and that it was not associated with other medical

conditions. Subsequent research has clarified that autism and related

conditions are distinctive disorders, are seen in all social classes, and

are strongly associated with some medical conditions, notably seizure

disorder, for which persons with autism are at increased risk. (4,5) Recent

work has strongly implicated genetic factors in causing the disease; it

appears that several genes are probably involved, and several promising

leads have been identified. (6)

Studies of treatments for autism and related conditions support the

importance of structured behavioral and educational intervention. (7)

Although no pharmacologic agent has proved curative, the treatment of

specific symptoms -- for example, with neuroleptic drugs -- can greatly aid

the child's ability to be helped by such programs. (8) Despite better

detection and improved services, autism is a major burden for children and

their families. It affects 1 in approximately 2000 children (2) and is

associated with some degree of mental retardation in about 75 percent of

cases. In slightly less than half of cases, affected persons never develop

communicative speech. (2) Understandably, parents often feel overwhelmed and

devastated by this diagnosis.

As noted by Sandler et al., (1) given the absence of a " cure, " it is

not surprising that a great number of treatments have been proposed; new

treatments, often accompanied by extravagant claims that they are

responsible for marked improvement or cure, are reported regularly, although

usually with minimal or inadequate data. In the case of secretin, the

impetus for interest in this drug was the reports in the broadcast and print

media about a young child with autism who improved dramatically after

receiving this gastrointestinal peptide during a study of pancreatic

function and the report of a small, uncontrolled case series. (9) The

widespread media attention and reports of dramatic improvement and cure led

many parents to seek secretin treatment for their children, and the ensuing

frenzy led to a black market for the drug. The interest in secretin was

remarkable, because it occurred in the absence of substantive data on its

potential benefit or safety; secretin had been approved by the Food and Drug

Administration only for single-dose use in the diagnosis of certain

gastrointestinal disorders. The safety of repeated administration of

secretin, which in its original form was derived from pigs, was unclear, and

the potential for sensitization after an initial infusion was a concern.

Sandler et al. found no significant improvement in various outcome

measures after a single infusion of secretin, as compared with placebo. In

addition, they note that in both the secretin group and the placebo group

there was a significant decrease in the severity of symptoms over time

(i.e., as a result of the nonspecific but important effects of being

involved in research). (10) None of the children treated with secretin had

treatment-limiting adverse effects in this study, nor did there seem to be a

delayed beneficial effect of the secretin infusion. The authors also note

the interest of many parents in continuing the use of the drug in their

children, even after the families obtained the results of this study. The

authors rightly note the limitations of their study. It will, of course,

need replication and extension, although the emerging results from other

trials of secretin for the treatment of autism appear to be similar. (11)

Lessons to be learned from the secretin phenomenon relate to the

relation between medicine and the news media, as well as to the nature and

treatment of autism. The extensive media attention when substantive

supporting data were absent was clearly premature and unfortunate. Parents

scrambled to obtain this " cure " for their children in the absence of data on

safety and efficacy -- aided, in some cases, by well-meaning, if not

well-informed, health care professionals. What makes an interesting

television program may not, of course, be the same as what makes good

science.

Although important findings do sometimes emerge unexpectedly and

dramatically, most of the time scientific progress is made slowly and

incrementally, as investigators replicate and extend results of previous

work. In autism, the progress in clarifying the role of genetic factors is

one such example. (12) Methodical and painstaking work, however, may not be

particularly newsworthy. Will the media devote as much attention and energy

to publicizing the negative results reported by Sandler and colleagues as to

the apparent initial success of secretin? From a policy perspective,

improved communication between journalists and investigators in the attempt

to provide accurate and honest information to parents is an important but as

yet often unachieved goal.

Given the seriousness of autism, the willingness of parents to pursue

unproven or emerging treatments is understandable. Treatments that have been

considered over the years include lysergic acid diethylamide, high-dose

glucocorticoids, psychosurgery, and injections of sheep-brain extract.

Clearly, it is important that parents know that some interventions have been

proved to be effective and helpful; such treatments should not be lightly

abandoned. Examples include intensive special education and attention to the

child's behavior to improve communication, speech, and other skills. The

attempt to educate professionals by developing guidelines for the diagnosis

and treatment of autism is welcome in this regard. (8,13) Unfortunately,

claims may be made on the basis of uncontrolled, single-case reports with

all the attendant problems (e.g., ambiguities regarding diagnosis and the

nature of the treatment and the fact that some children improve without

intervention). Pursuing unproven treatments risks depleting the financial

and psychosocial resources of families. (14,15) It is important that

physicians help families make informed decisions about treatment for autism.

The nonspecific gains in behavioral and developmental functioning that

can be realized as a result of being involved in research deserve particular

mention. These gains highlight the importance of controlled research, as

well as the potential of systematic attention in improving the lives of

people with autism. (10)

Fred R. Volkmar, M.D. Yale University School of Medicine New Haven,

CT 06520

[Respond, if you please, to FEAT@... ]

* * *

APA Response to Congressional Concerns

[Dr. Appelbaum, issued a statement in response to U.S. House of

Representatives hearing on, " Do Current Federal Regulations Adequately

Protect People Who Participate in Medical Research? " ]

Dr. Appelbaum, Vice President of the American Psychiatric

Association (APA) and Secretary of its Ethics Appeals Board, issued the

following statement in response to U.S. House of Representatives Committee

on Government Reform Subcommittee hearing on, " Do Current Federal

Regulations Adequately Protect People Who Participate in Medical Research? "

" My research over the last two decades has taught me that if we are to

master the diseases that affect the brain, we must have the assistance of

persons who unfortunately suffer from mental disorders. However the

interests of the participants in the research project come first. If

research cannot be performed without violating the rights of participants,

it should not take place.

Effective research is the key to more effective treatment of these

disorders and to reduction of the suffering they cause. The introduction of

the first effective treatments for schizophrenia and other psychotic

disorders in the 1950s permitted, for the first time in history, the

long-term treatment of persons with these disorders in the community, rather

than in institutions.

The American Psychiatric Association endorses as its starting point in

addressing the complexities of this area the dual importance of three key

principles:

-- Minimize the risk to those persons who volunteer to participate in

research studies

-- Maximize participants' knowledge of what their involvement will

entail

-- Enforce safeguards required for permitting persons who lack

decision-making capacities to be entered into research projects.

Lastly, questions have been raised about the appropriateness of

studies in medicine, including mental health research, involving

discontinuation of medication. Safeguards and protections for patients are

essential. Patients should be told the possible consequences of stopping

medication and they must provide competent, informed consent and understand

the criteria for reinitiating of treatment. Medication discontinuation

studies have played and will continue to play a critical role in developing

many new medications that can transform and save thousands of patients'

lives. "

* * *

Ritvo First Reported Chromosome 13 and Recessive Form of Autism

To set the record straight -- I'm pleased and proud to let you know

that my husband, Ritvo, MD Professor Emeritus, UCLA medical school,

established the UCLA Registry for the Genetic Studies of Autism in 1980,

despite a paucity of funding (autism was a little recognized, " orphan

disease " twenty years ago). He set out to discover if genetic factors could

cause autism.

He traveled tens of thousands of miles through out the US and Europe

to personally diagnose and obtain blood samples from multiple incidence

families (doing all this, I might add, while he was suffering from

degenerative heart disease which lead to his recently receiving a heart

transplant).

Among the main published findings based on the UCLA Registry for

Genetic Studies are 1) chromosome 13 was twice identified as a candidate

gene. First via gene mapping 1985, and more specifically via studying a

multi-incidence family with autism, retinoblastoma, and reduced esterase

activity. 2) evidence for autosomal recessive inheritance of autism was

found in 46 families with multiple incidences of autism 3) in 21 of 22 sets

of identical twins (95% ) both had autism whereas only 4 of 17 (24%) non

identical twin pairs both had autism (this fits with a recessive model of

inheritance in these families) in the general population 4) the chances of

having a second autistic child if you already have one increases to

approximately 8 percent.

[Mrs. Ritvo]

____________________________________________________________

editor: Lenny Schafer schafer@... | * Not FEAT

eastern editor: , PhD CIJOHN@...

*** WHY YOU MAY WANT TO SUBSCRIBE NO COST (or unsubscribe) ***

To FEAT's Daily Online Newsletter: Daily we collect features and news of

the world of autism as it breaks. Subscribe: http://www.feat.org/FEATNews

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