Reading a discussion in the recent comments, I ran across a reference I hadn’t seen. It was a report [ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth] published in 2006 – yet another meta-analysis of the Clinical Trials of SSRIs in adolescents, and something of a critique of Hammad’s FDA meta-analysis [PowerPoint]:
ACNP Task Force report on SSRIs and suicidal behavior in youth.
by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD.
Neuropsychopharmacology. 2006 31[3]:473-492.
[Full Text On-Line]
Abstract:
This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.
The American College of Neuropsychopharmacology is a primo organization for neuroscientists and psychopharmacologists, publishing Neuropsychopharmacology. And as long as I seem to be having a link-fest, let me just create us a little reference library for this post:
- [The 1991 hearings on suicidality with Prozac]
FDA PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE September 20, 1991 - [The 2004 FDA Hearings that approved the Black Box warning]
FDA HEARING: September 13, 2004 Transcript (PDF) (Word)
FDA HEARING: September 14, 2004 Transcript (PDF) (Word) - [The FDA Meta-Analyses: Hammad and Kaizar]
Hammad’s FDA meta-analysis
Do antidepressants cause suicidality in children? A Bayesian meta-analysis - [Bridge’s Meta-Analysis]
Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment - [The Institute of Medicine Conference]
CNS CLINICAL TRIAL: SUICIDALITY AND DATA COLLECTION - [ACNP Task Force]
ACNP Task Force report on SSRIs and suicidal behavior in youth
So, back to the Task Force report by the American College of Neuropsychopharmacology, the list of Task Force Members certainly had some beyond remarkable choices: the senior author on all of Robert Gibbons papers on the subject [Mann]; three authors from Keller’s Study 329 paper [Ryan, Emslie, Wagner]; an author on the Zoloft, Paxil, Prozac, and Celexa adolescent trials [Wagner]; an author of two Prozac, one Paxil, and the TADS adolescent trials [Emslie]; and a heavy smattering of other industry affiliations:
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J John Mann, MD
Task Force Co-Chair
The Paul Janssen Professor of Translational Neuroscience in Psychiatry and Radiology, Columbia University College of Physicians and Surgeons
Chief, Department of Neuroscience,
New York State Psychiatric Institute
ACNPIndustry Affiliations:- Consultant: GlaxoSmithKline, Pfizer, 2001 (expert trial witness)
- Grants/Research Support: PET ligand development grant from Pfizer (2003), Beta-amyloid imaging grant from GlaxoSmithKline (2005)
- Attended a 2002 GlaxoSmithKline Advisory group meeting on lamotrigine
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Graham Emslie, MD
Task Force Co-Chair
Chief, Division of Child and Adolescent Psychiatry and Professor of Psychiatry,
The University of Texas Southwestern Medical Center at Dallas
ACNPIndustry Affiliations:- Consultant/Speaker’s Bureau: Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, McNeil, Otsuka, Pfizer, Inc. Wyeth-Ayerst
- Grants/Research Support: Eli Lilly, Novartis, Organon
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Ross J Baldessarini, MD
Professor of Psychiatry and Neuroscience, Harvard Medical School
Director, Laboratories for Psychiatric Research, Mailman Research Center
Director, Bipolar & Psychiatric Disorders/Director, Psychopharmacology, McLean Hospital
ACNPIndustry Affiliations:- Consultant/Research Collaborator: Auritec Laboratories, Eli Lilly Laboratories, IFI SpA, Janssen Pharmaceuticals, JDS Corporation, NeuroHealing Pharmaceuticals
- Grants/Research Support: Eli Lilly Laboratories (former grant recipient), Janssen Pharmaceuticals
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William Beardslee, MD
Psychiatrist-in-Chief and Chair, Children’s Hospital Department of Psychiatry
Professor of Child Psychiatry, Harvard Medical SchoolNo Industry Affiliations -
Jan Fawcett, MD
Professor of Psychiatry, University of New Mexico
ACNPIndustry Affiliations:- Consultant: Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Laboratories, Janssen Pharmaceutica, GlaxoSmithKline, Merck & Co. Inc., Pfizer, Inc., Pharmacia & Upjohn, Wyeth-Ayerst Laboratories
- Speaker’s Bureau: Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer/Roerig, Pharmacia, GlaxoSmithKline, Solvay Pharmaceuticals, Inc., Wyeth-Ayerst Laboratories
- Grants/Research Support: National Institute of Mental Health, Abbott Laboratories, Astra Zeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Organon, Pfizer, Inc., Wyeth-Ayerst Laboratories
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Fred Goodwin, MD
Research Professor of Psychiatry and Director, Psychopharmacology Research Center, George Washington University
ACNPIndustry Affiliations:- Consultant: Glaxo, Lilly, Pfizer, Bristol Myers Squibb, Solvay. Elan, Novartis
- Speakers Bureau: Bristol Myers Squibb, Solvay, Glaxo, Pfizer, Janssen, Lilly, AstraZeneca, Grants/Research Support: Abbott Laboratories, Glaxo, Solvay, Janssen, Pfizer, Lilly, Forest, Sanofi,
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Andrew C Leon, PhD
Professor of Biostatistics in Psychiatry and Professor of Public Health,
Weill Medical College of Cornell University.Industry Affiliations:- Consultant: Cyberonics, Inc., Cortex Pharmaceuticals, Pfizer.
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Herb Meltzer, MD
Professor of Psychiatry & Pharmacology, Director Division of Psychopharmacology
President, Collegium Internationale Neuropsychopharmacologicum (CINP),
Vanderbilt University Medical Center
ACNPIdustry Affiliations:- Consultant, Speaker’s Bureau, Honorarium, Grant/Research Support: Eli Lilly, Pfizer, GlaxoSmithKline, Janssen, AstraZeneca
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Neal Ryan, MD
Professor of Psychiatry, Western Psychiatric Institute & Clinic, University of Pittsburgh
ACNPIndustry Affiliations:- Consultant: GlaxoSmithKline (designed study and a performance site for the GSK study of paroxetine in adolescents and was second author on the resulting publication as well as a co-author on related letters to the editor including one letter related to suicidality assessment in that study)
- Consultant: GlaxoSmithKline (examination of their data related to suicidality in their aggregate paroxetine data.)
- Consultant (design of studies of antidepressants in youth): Pfizer, GSK, and Wyeth
- Primary Investigator: Wyeth (Pittsburgh performance site for the study of Venlafaxine and children.)
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David Shaffer, MD
Professor of Child Psychiatry, and Professor of Psychiatry and Pediatrics,
Columbia University College of Physicians and Surgeons
Director, Division of Child Psychiatry, New York State Psychiatric InstituteIndustry Affiliations:- Consultant: Hoffman la Roche, Wyeth (expert trial witness)
- Consultant: GlaxoSmithKline (on the matter of paroxetine and adolescent suicide)
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Karen Wagner, MD, PhD
Director, Division of Child and Adolescent Psychiatry,
Professor and Vice Chair, Department of Psychiatry and Behavioral Sciences,
University of Texas Medical Branch, Galveston
ACNPIndustry Affiliations:- Consultant: Abbott Laboratories, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest Laboratories, Glaxo-Smith Kline, Janssen, Novartis, Otskua, Pfizer, UCB Pharma, Wyeth-Ayerst
- Speaker’s Bureau: Abbott Laboratories, Eli Lilly and Co., Forest Laboratories, Glaxo-Smith Kline, Janssen, Novartis, Pfizer Inc.
- Advisory Board: Abbott Laboratories, Eli Lilly and Co., Forest Laboratories, Glaxo-Smith Kline, Janssen, Novartis, Otsuka, Pfizer, UCB Pharma, Wyeth-Ayerst
- Research Support: Abbott, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Organon, Pfizer, Wyeth-Ayerst, National Institute of Mental Health
The Task Force said:
SUMMARY OF FINDINGSDepression in youth is a serious public health problem and the leading cause of suicide. Suicide is the third leading cause of death among 15–24-year olds in the United States and the leading cause of death in that age group in several other countries. As suicide most commonly occurs in untreated depression, diagnosis and treatment of juvenile depression require urgent attention.
The ACNP Task Force reviewed published and unpublished data to evaluate the benefits and risks of SSRIs and other new generation antidepressants for adults and youth under 18 years of age. The Task Force found that only fluoxetine showed strong statistical evidence of efficacy in treating depression in youth in RCTs. No other SSRI and nonSSRI new antidepressant has two controlled trials that demonstrate efficacy. Differences in drug effectiveness across clinical trials may result from real differences in efficacy or from differences in methodology. We recommend an additional study of potential antidepressants in children and adolescents by RCTs that include fluoxetine as the only established reference compound. The Task Force also found that the category of antidepressants known as tricyclics have not been proven to be effective antidepressants in youth. Other forms of treatment, including psychotherapies, were found to be not widely available to youth, and have insufficient data [such as effective in two controlled studies] to support their routine use in pediatric depression.
The Task Force concluded that SSRIs and other new generation antidepressant drugs, in aggregate, are associated with a small increase in the risk of AE reports of suicidal thinking or suicide attempts in youth. The evidence for this comes from the FDA meta-analyses of all pediatric RCTs of antidepressants. This effect is quite variable across SSRIs and it is not clear if that variance is a measurement error or represents a real difference between medications. Systematic questionnaire data do not identify a risk for more suicidal ideation on SSRIs, raising concerns over ascertainment artifacts in the AE report method. Three other lines of evidence in youth, epidemiology, and autopsy studies, and recent cohort surveys [Valuck et al, 2004; Simon et al, 2005], do not support the hypothesis that SSRIs induce suicidal acts and suicide, instead indicating a possible beneficial effect, and that a negligible number of youth suicides are taking antidepressants at the time of death.
I’ll spare you the rant about conflicts of interest – you can fill it in without any help from me. Their SUMMARY, and the RECOMMENDATIONS at the end of the report are consistent with the findings. I have two complaints other than to say that the make-up of the Task Force itself is an insult to any principle of medical ethics that I have ever known. First, they minimize the suicidal thinking. And second, they say:
The Task Force recommends continued use of fluoxetine as an effective and readily available treatment for major depression in youth. We believe other SSRIs need further testing to establish efficacy by use of RCTs preferably including fluoxetine as a reference compound. We urge clinicians treating depressed youth to ask about suicide, suicidal thinking, and plans for suicide. Ongoing monitoring of suicidal thoughts in patients treated with antidepressants is necessary. To facilitate that process, the FDA has issued a Proposed Medication Guide: About Using Antidepressants in Children or Teenagers, which should be made available to patients and parents alike. Given that the FDA is not empowered to make treatment recommendations, professional organizations must issue comprehensive treatment guidelines so that patients will continue to receive appropriate medications when indicated.
If there were a statistically significant association between SSRIs and suicide attempts or completed suicides, the drugs would have more than a Black Box warning. They would be banned for children. The warning is based on well documented case reports and on the experience of clinicians who follow depressed adolescent patients, not statistical population data. The contrast between this injunction, "professional organizations must issue comprehensive treatment guidelines so that patients will continue to receive appropriate medications when indicated" and the failure of these same "professional organizations" to either censure or punish members who participate in ghost-written, deceitful publications of drug studies claiming unproven efficacy is striking. Do they not notice that there are three such people on their Task Force? Their point "the FDA is not empowered to make treatment recommendations" is true, but it doesn’t necessarily follow that "professional organizations must issue comprehensive treatment guidelines so that patients will continue to receive appropriate medications when indicated." Treatment Guidelines have been a major portal for the inappropriate intrusion of the pharmaceutical industry into the practice of psychiatry. The TMAP/CMAP scandal is a classic example. It would be hard to convince me that this ACNP recommendation isn’t also an example. The increments of efficacy shown for SSRIs in adolescents, when present at all, are clinically microscopic and hardly justify these comments…
“but it doesn’t necessarily follow that “professional organizations must issue comprehensive treatment guidelines so that patients will continue to receive appropriate medications when indicated.”
when did professional organizations take on the role of issuing comprehensive treatment guidelines.?
i am sure the insurance industry values this function
There’s an assumption in all these studies that needs to be unpacked. When they say ” Depression in youth is a serious public health problem and the leading cause of suicide.” There is an assumption that depression is a single entity rather than a final common pathway or a huge blanket term that covers many life circumstances. Most of the “depression” I see in my clinical setting is clearly a response to loss, incapacity, frustration, marginalization, abuse, and the like. Any meaningful treatment would involve removing or ameliorating the life circumstances. None of this would logically involve medication. To label depression as the prime mover in suicide is short-sighted at best.
Psychiatry need not feel too alone
“Sadly, none of them is interested in making drugs for rare conditions or, say, for an infectious disease in countries with no money, because it’s not a big market. Nor are they interested in developing drugs for conditions like Alzheimer’s or Parkinson’s disease because it too difficult and there’s not money to be made quickly.
“It has become interested only in the immediate, in short term gains. On Wall Street, the pharmaceutical industry is third after petrol and banking, and each year it increases by 20%. It’s more profitable than mining for diamonds.”
Asked to explain French people’s apparent dependence on medication, Even said: “For the last 40 years patients have been told that medicines are necessary for them, so they ask for them. Today we have doctors who want to give people medicines and sick people asking for medicines. There’s nothing objective or realistic about this.”
He added: “There is nothing revolutionary in this book. This has all been known for some time.”
http://www.guardian.co.uk/world/2012/sep/14/french-doctors-drugs-useless-dangerous?INTCMP=SRCH
If this is the work product of a top tier society in the field, at least according to 1BOM and Dr. Carroll, then may God help the field. Ryan and Wagner in the JAACAP paper turn that data in one RCT into: “Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.” They subsequently in this paper state ” Other forms of treatment, including psychotherapies, were found to be not widely available to youth, and have insufficient data [such as effective in two controlled studies] to support their routine use in pediatric depression.” No double speak as they use with the summary of the SSRIs, just no support of their routine use.
Dr. Ryan appears convinced that children will be suffering a disservice if they do not have something widely available (nothing can rival drugs in this regard) and is committed to data being presented in such a way that sensitivity of detection is prioritized and that undertreatment is minimized. So be it. But it seems that most work products he has collaborated on (the 2001 JAACAP paper, the 2006 ACNP paper, even as more background participant in the 2006 GSK safety paper) to have something that supports that agenda. He was mentored by Dr. Joaquin Puig-Antich who fought hard for people to recognize the true suffering of children with major depression. Given psychoanalysis’ earlier hegemony, and child work’s more minor status, it was probably a valid and difficult fight to have the need for biological treatment of depression in some children recognized and acted upon effectively. In the cases of those children who truly need medication intervention, the inherent (at least in the past) tendency of pediatricians to avoid the aggressive use of medications may have also necessitated that researchers bang the drum more loudly to make them aware of this need. There is also no “test” that makes it evident. This background appears to infuse much of Dr. Ryan’s work.
If I had to hazard a guess, and the motivation of others can always only be a guess, it would be that those who know Dr. Ryan would not view this dedication as havin been influenced by pharma. However, I wonder if they would be quick to discount the idea of him being a zealot. If he is that comes with advantages and disadvantages. As it does for professional organizations.
Because if taking drug company money, and the compromises that come along with it, gets more tools (ie meds) into the hands of primary care providers and gives you a megaphone (pharma marketing) with which to reach them, then you just do it. You use statistics to get the findings you know should truly be there. You don’t highlight morbidity with the drugs because that pales in comparison to the mortality you’re trying to fight. Bringing up the point that a “Teen Screen” may have too low a specificity is a hardening back to the bad old days when we didn’t recognize that childhood mental illness is common and effectively addressable with something primary care docs have readily at hand, drugs. This is not simply self-interest. Child psychiatry is sending the message that a primary care provider can adequately assess childhood depression and start and monitor treatment (has to be meds because they couldn’t deliver anything else). The message is DO NOT refer on for psychotherapy or even to child psychiatrists because the resources aren’t there. I.e. the kind of depression in kids that necessitates either medication intervention or fairly skilled psychotherapy is so common that you should start meds yourself.
This is a message public health and pharma wants to hear and they are happy to have money flow to those who come from that vantage point.
Part of the danger is you get a situation like what happened with paroxetine. My bet is that many psychiatrists who knew what they were doing realized that paroxetine’s very short half life was a problem, particularly in adolescents, both in terms of side effects while on it, and in terms of discontinuation problems. Of you look at that pamphlet pf the Wagner talk included among the DOJ exhibits (the one they used for marketing) there were psychiatrists in the audience saying as much while Wagner touted the benefits of the drug. Wagner got herself flown to resorts as a KOL to tout her message of the benefits of paroxetine’s short half life to large numbers of child psychiatrists, and had SKB staff ghostwrite her poster for NCDEU.
Drs. Ryan and Wagner let GSK use Study 329 in their turf battle with Lily. And appear to have involved themselves in the later 2006 presentation of the data at least in part, if Keller’s email to them is to be believed, out of not wanting to be judged in a way they thought unfair. Ryan had earlier not wanted SKB to reach out to more sites (which come to think of it could have increased the power of the study) as that could have professional consequences for him if sites were rejected.
Those of you who believe that Drs. Ryan an Wagner’s approach to the data on paroxetine resulted in benefit to SKB/GSK raise your hands.
Keep your hands up if you believe it resulted in benefit to Drs. Ryan and Wagner. Professionally, financially, their agendas, etc.
Finally, keeping in mind the point that many of the kids put on paroxetine might instead have been placed on fluoxetine instead, who believes it resulted in benefit to kids?
Who still has their hand up?
If you don’t, then maybe this is the problem with there not being better checks and balances in the system. Especially if you are someone relying on consensus statements as don’t have the expertise/time to review all the primary papers.
What stopped Ryan and Wagner from making the point in 2001 that maybe fluoxetine was just a better choice than both paroxetine and imipramine for the treatment of depression in adolescents? The 2001 paper did NOT compare paroxetine to imipramine directly and that the study was not designed to do so. They are explicit that both were compared to placebo. Yes, they had the choice to feel that this was from methodological differences. But they were force titrating Imipramine to a minimum of 200mg even if effective at a lower dose and as co-author Geller pointedly out this resulted in higher side effects. They were comfortable in touting paroxetine over imipramine despite those caveats.
Given how weak the efficacy data actually was for paroxetine, and that the safety data for it was concerning, why did Ryam and Wagner choose to not include in the discussion section of the JAACAP paper a conclusion that, looking at their study in the context of the literature at the time (keep in mind that by 2001/2 Lily had submitted enough findings to the FDA that the FDA was satisfied in giving it an indication in kids for MDD), that fluoxetine would be a better first line choice for clinicians with paroxetine possibly second-line.
There can be a lot of hand waving.
But ask yourself this:
Ask yourself if kids really would have suffered if Lily reps could go out there and say that fluoxetine was likely a better first line choice for adolescents than paroxetine. Ask yourself whether some kids went on paroxetine, hated the side effected and discontinuation problems with the short half life (which they may never have been adequately warned about if their MD was not adequately aware), and never wanted to go to try another SSRI such as fluoxetine.
Then look at the rest of 1BOM’s posts on this site over the past few weeks if you haven’t yet.
Do you really believe the data wasn’t there to suggest paroxetine was a weaker first line choice than fluoxetine for adolescents with MDD?
What does common sense tell you about the decision not to present that viewpoint in the conclusion of the 2001 paper, or Wagner’s decision in her talks to imply otherwise.
Do you think kids would have been better served if GSK reps couldn’t have used the 2001 paper, and Wagner’s presentation, to convince doctors to use paroxetine first-line ahead of fluoxetine in the teens they were treating?
Thanks to Altostrata for helping me realize that that is what the 2001 paper and Wagner’s talks achieved, at least in part. Kids that were going to be put on an SSRI being put first on paroxetine instead of fluoxetine.
To beat this dead horse, whether or not you believe SSRIs are important to the treatment of some kids or should be forbidden across them all, you can all believe that they may not be equivalently good or equivalently bad. It’s important to know about this wherever you fall on the issue.
Are there clinicians, researchers, families out there that think that, on the whole, paroxetine is a better first line choice for a teenager who is thought to be depressed? I.e., if you think they should get an SSRI should it be first line OR if you think they will mainly be suffering through side effects and withdrawal would this be the SSRI you’d most want them subjected to? I suspect that both sides would still NOT pick paroxetine over fluoxetine.
Study 329 could have been handled by Drs. Ryan and Wagner in such a way that many more kids would have been started on fluoxetine first, ahead of paroxetine. I doubt clinicians would have considered that a bad outcome. Instead they explicitly and consistently (even in the face of numerous objections) chose to handle it in a way that had the reverse effect.
Who believes that was better for kids, no matter where you stand on the broader issues?
“ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth” — is this one of those pharma-sponsored task forces? I believe it was published (Nov 2005) prior to adoption of reporting pharma sponsorship of journal articles.
Altostrata,
In the executive summary they explicitly specify that there was no financial support from the pharmaceutical industry for the task force. Looking at the list of task force members selected that point seems largely moot.
Thanks again for having earlier pointed out that Ryan’s and Wagner’s actions most likely led to the use of paroxetine instead of fluoxetine more than anything else.
FYI
Posted: Sun, Sep. 16, 2012, 3:01 AM
Whistle-blower honored in Texas, fired in Pa.
Dealings between public employees and drug firms were similar in both states.
Reaction was very different.
http://www.philly.com/philly/business/20120916_Whistle-blower_honored_in_Texas__fired_in_Pa_.html?viewAll=y
Following up on Dr. Ryan in relation to Study 329 and GSK Marketing using it to convince doctors to use paroxetine first-line with adolescents when they might otherwise have used fluoxetine. AACAP awarded him Distinguished Fellow status between 2010-2012. We are not talking about censure. We are talking about the strongest endorsement the academy bestows on its members. This, even aside from having been picked by AACAP to be on the Consensus Building Panel for Conflicts of Interest in 2008.
GSK fought a turf battle with Lily over the medication of adolescents with depression. Dr. Ryan aided them in this turf battle.
There is the information in the DOJ complaint, the promoting of first-line use of Paxil over Prozac in adolescents by GSK with the aid of Dr. Wagner, and then there is this:
http://dida.library.ucsf.edu/pdf/vru38h10
Carefully read paragraph one and the last three paragraphs of that letter.
Note also that this letter is from end of January 2002, just shortly after Prozac received FDA approval for use in MDD in kids.
Dr. Ryan has never publicly expressed any regret whatsoever on his handling of Study 329 and it’s subsequent use by GSK Marketing to promote the use of paroxetine in adolescents over other approaches (including fluoxetine – what GSK’s documents indicate was their primary concern). We are not just speaking of then, he has never publicly expressed regret at his actions/silence in regards GSK marketing’s use of Study 329 to promote paroxetine over fluoxetine as first-line treatment in kids. Nor has Dr. Wagner for playing a central role in that effort.
This is what AACAP has recognized with Distinguished Fellow status.
As an aside, Dr. DelBello was also accorded distinguished fellow status by AACAP during this same time. And, was also selected for the consensus panel along with Dr. Ryan in 2008 (she had the distinction of also sitting on the AACAP consensus panel for conflicts specific to researchers that same year).
Given the level of interest Paul Thacker has shown in both Study 329 and Dr. DelBello it almost seems like receiving the benefit of Paul Thacker’s attention, and expressing no regrets, is of benefit to one’s standing within the academy.
You’re welcome, Annonymous. Please allow me to point out that, compared to Prozac, Paxil has a worse adverse effect profile in adults and is notorious for withdrawal syndrome. It’s not likely children are any less affected. The Paxil pushers have very dirty hands.