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Letters to the Editor

Am JPsychiatr y 167:11 , November 2010 ajp.psychiat ryonl ine.org 1407

Questions on Conflict of Interest

TOTHEEDITOR: We are writing to inquire about how theJour-

nalhandles issues of conflict of interest, both financial and

intellectual. We raise these questions in the interest of stimu-

lating discussion and encouraging greater transparency, not

because we believe there is necessarily one right answer to

any question.What is the operational basis of the Editors evaluation for

possible influence from disclosed financial relationships? Given

that such influences can be difficult for nonspecialists to detect

and may operate beyond the awareness of authors themselves,

what criteria are used to judge whether influence has occurred?

1) Is potential conflict of interest one of the criteria taken

into account when inviting authors of editorials or review

articles? For example, if faced with a choice of several possi-

ble authors, does theJournalgive preference to those without

potential conflicts of interest, all other factors being equal?

2) Does the Journals conflict of interest policy take into

account so-called intellectual conflict of interest as well as

financial conflict of interest? Some professional societies arebeginning to pay attention to this type of conflict in relation-

ship to practice guidelines (1).

Restrictions on authorship have costs of their own, including

exclusion of the contributions of experts in a field, and should

not be undertaken lightly. However, the argument for prefer-

ring authors without financial relationships with industry

seems particularly strong in the case of editorials and reviews,

the value of which resides principally in the reliance that read-

ers can place on the opinions of the authors. Advocating norms

of this sort is not to suggest that industry relationships are nec-

essarily problematic in themselves, but recognizes that certain

activities may be incompatible with playing an active role in

developing treatment recommendations for the field, as is the

case for the development of DSM-5 (2).

References

1. Guyatt G, Akl EA, Hirsh J, Kearon C, Crowther M, Gutterman D,

Lewis SZ, Nathanson I, Jaeschke R, Schunemann H: The vexing

problem of guidelines and conflict of interest: a potential solu-

tion. Ann Intern Med 2010; 152:738741

2. http://www.dsm5.org/about/Pages/BoardofTrusteePrinciples.

aspx

DAVID A. GORELICK, M.D., PH.D.

Baltimore, M.D.PAUL S. APPELBAUM, M.D.

New York, N.Y.

Dr. Gorelick is supported by the Intramural Research Pro-

gram, National Institute on Drug Abuse, National Institutes of

Health. Dr. Appelbaum has an equity interest in COVR, Inc.

This letter (doi: 10.1176/appi.ajp.2010.10070978) was accepted

for publication in August 2010.

Note From the Editor

For the Treatment in Psychiatry series and other clinical research

and treatment articles in the Journal, we solicit articles from senior

authors who can inform our experienced clinical readership about

their current thinking on the treatment of difficult clinical problems

that do not yet have fully resolved solutions. Accordingly, we often

choose authors who are directly involved in the development of

new treatments through leadership of relevant National Institutes of

Health and industrial clinical trials, because they have the broadest

and most relevant experience. We recognize that a risk of this choice is

that the authors who are most involved in the development of a new

treatment may also have conflicts of interest, both commerical and

intellectual.

We therefore invite Editorials on many of our articles from other

experts in the field to highlight the significance as well as the limita-

tions of the articles and to place them in perspective for readers whoare not experts themselves. While the absence of obvious conflicts,

such as financial support from a sponsoring pharmaceutical com-

pany, is one criterion that we consider in the choice of editorialists,

many experts, by virtue of their work in a field, have conflicts of inter-

est themselves.

TheJournalhas required full disclosure of competing interests since

2006. We recognize that this information, although necessary, may not

be sufficent for readers to detect specific biased statements. Each paper

is assessed by several expert reviewers in a first stage of review and then

in a second stage by the Deputy Editors and other members of the Edito-

rial Board. Conflict of interest is considered in these evaluations. Claims

beyond what is supported by the data lead to significant revision or rejec-

tion of the paper. After publication, Letters to the Editor from interested

readers like Drs. Gorelick and Appelbaum can also identify incorrect or

biased statements in articles.As Editor, I have agreed not to accept any financial support from

pharmaceutical companies. In my role, I read and review each article in

theJournaland all comments from the review process to add my assur-

ance that the important new information in each article that we publish

for psychiatrists and their patients is as independent and authoritative

as possible.

ROBERT FREEDMAN, M.D., EDITOR

Schizophrenia and Obsessive-Compulsive Disorder

TOTHEEDITOR: In the July 2010 issue of the Journal, Carolyn I.

Rodriguez, M.D., Ph.D., et al. (1) presented an interesting case

illustrating the complexities of co-occurring psychotic and

obsessive-compulsive disorders (OCD). The authors shouldbe commended for their careful review of the differential

diagnosis and treatments for a patient presenting with these

intertwined symptoms.

In the case study, the patient was found to have manifested

obsessive compulsive symptoms prior to his first psychotic

episode. Such a presentation is consistent with the results of a

meta-analysis we conducted regarding the temporal relation-

ship of OCD and schizophrenia in patients suffering from both

disorders (2). Our analysis showed that in patients diagnosed

with both disorders, OCD tends to precede schizophrenia by

1 year. While our study did not find this result to be statisti-

cally significant, it did nearly reach significance (p=0.066),

suggesting the potential for statistical significance in stud-ies with a larger sample size. Clearly, Dr. Rodriguez et al.s

suggestions for longitudinal studies of young people at risk

for psychosis or OCD would provide for much needed insight

into the epidemiology and clinical phenomenology of co-

occurring obsessive compulsive and psychotic symptoms.

In their discussion of the potential adverse drug-drug

interactions between clozapine and fluvoxamine, the authors

appropriately mentioned cytochrome 3A4. We would like to also

mention that cytochrome 1A2 is even more significantly involved

in the metabolism of clozapine (3). As a strong inhibitor of cyto-

chrome 1A2, combining fluvoxamine with clozapine in patients

suffering from both OCD and treatment-resistant schizophrenia

may produce serious adverse effects. Further, nicotine in tobacco

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LETTERS TO THE EDITOR

1408 ajp.psychiat ryonl ine.org Am JPsychiatr y 167:11, November 2010


for publication in June 2010.

Response to Eppel Letter

TOTHEEDITOR: We appreciate Dr. Eppels thoughtful comments.

Our National Institute of Mental Health study was originally

designed to compare the safety and efficacy of long-term fluox-

etine versus lithium monotherapy versus placebo in preventingrelapse and recurrence of bipolar II major depressive episode.

We hypothesized that fluoxetine monotherapy would be supe-

rior to lithium monotherapy, with a similar hypomanic mood

conversion rate. Survival analysis indicated that the mean time

to relapse was 249.9 days with fluoxetine (N=28), 156.4 days

with lithium (N=26), and 186.9 days with placebo (N=27). The

hazard of relapse was significantly lower with fluoxetine versus

lithium, with the estimated hazard for lithium being 2.5 times

greater than the estimated hazard for fluoxetine.

Dr. Eppels use of an absolute proportion of patients who

remained well at the end of the study appears to combine

initial response in study phase I with failure to relapse in

phase II. For example, he suggests that the relapse rate, cal-

culated as the proportion of the 148 patients who entered

phase I and completed the entire study, is 78.4%. However, we

would suggest that the relapse rate should not be calculated

among the 148 patients who entered phase I, since patients

were depressed (or in a relapsed state) at the start of phase I.

Rather, the comparison of relapse rates and time to relapse

between treatment groups should begin after the completion

of phase I (i.e., at the start of phase II, when the subgroup of

patients who responded to initial fluoxetine monotherapy

were randomly assigned to treatment in phase II).

Dr. Eppel also notes that only 21.6% of the original 148

patients would be deemed well after 50 weeks (in phase II).

However, only 81 of the original 148 patients in phase I were

ultimately randomly assigned into phase II and had at leastone additional measurement in phase II. If we had wished to

base an estimate of the probability of doing well after 50 weeks

of treatment in phase II on the original 148 patient sample, we

would have needed to follow all 148 patients until the end of

the study, since some of the patients who had not responded

by the end of phase I could have responded by the end of

phase II.

Although our study was not designed to combine the results

of phases I and II, we could estimate the following probabili-

ties based on the combined results of both phases: 1) the

probability of responding to fluoxetine monotherapy during

phase I and failing to relapse in phase II during treatment

with fluoxetine; 2) the probability of responding to fluoxetinemonotherapy during phase I andfailing to relapse in phase

II during treatment with lithium; and 3) the probability of

responding to fluoxetine monotherapy during phase I and

failing to relapse in phase II during treatment with placebo.

We can estimate each of the aforementioned probabilities

using conditional probabilities. For example, the probability of

responding to fluoxetine monotherapy during phase I and fail-

ing to relapse in phase II during treatment with fluoxetine mono-

therapy can be calculated as the product of two probabilities:

Pr (response to fluoxetine monotherapy during phase I) Pr

(failure to relapse in phase II during treatment with fluoxetine

given that the patient responded to treatment with fluoxetine

during phase I), where Pr(A) indicates the probability of A.

is an inducer of cytochrome 1A2 and may lead to attenuation of

the efficacy of clozapine unless the dose is increased.

References

1. Rodriguez CI, Corcoran C, Simpson HS: Diagnosis and treat-

ment of a patient with psychotic and obsessive-compulsive

symptoms. Am J Psychiatry 2010; 167:755761

2. Devulapalli KK, Welge JA, Nasrallah HA: Temporal sequence of

clinical manifestation in schizophrenia with co-morbid OCD:

review and meta-analysis. Psychiatry Res 2008; 161:105108

3. Chetty M, Murray M: CYP-mediated clozapine interactions:

How predictable are they? Curr Drug Metab 2007; 8:307313

KAVI DEVULAPALLI, B.A, M.P.H.

Cleveland, OhioHENRY A. NASRALLAH, M.D.

Cincinna ti, Ohio

Dr. Nasrallah has received research grant support from For-

est, Janssen, Otsuka, and Shire; and he has served on the advi-

sory board or speakers bureau of AstraZeneca, Janssen, Merck,

Novartis, Pfizer, and Sepracor. Dr. Devulapalli reports no finan-

cial relationships with commercial interests.


for publication in August 2010.

Antidepressant Use in Bipolar Disorder: Con-tinuing an Age-Old Debate

TO THE EDITOR: In their article published in the July 2010

issue of the Journal, Jay D. Amsterdam, M.D., and Justine

Shults, Ph.D., (1) add more fuel to the three-decades old

debate between those who advocate minimal use of antide-

pressants in the treatment of bipolar disorder and those who

favor maximal usage (2). The authors are to be congratulated

for addressing critical methodological parameters in theirstudy: adequate duration (50 weeks) and inclusion of efforts

to identify subsyndromal hypomania. Their results are never-

theless surprising. For clinicians and patients, the key ques-

tion remains whether these results are clinically significant.

Eleven of 28 patients (39.2%) in the fluoxetine group had not

relapsed at the end of the study. Even if we extrapolate this propor-

tion to all 83 patients in the second phase of the study, the result

is that only 21.6% of the original 148 patients would be deemed

well at 50 weeks. This is a relapse rate of 78.4%. From the patients

point of view, these are very poor odds and do not represent a via-

ble treatment option. The best evidence to date is that antidepres-

sants have only a limited role in the treatment of bipolar disorder

when long-term stability is seen as the goal of treatment (2).References

1. Amsterdam JD, Shults J: Efficacy and safety of long-term fluox-

etine versus lithium monotherapy of bipolar II disorder: a ran-

domized, double-blind, placebo substitution study. Am J Psy-

chiatry 2010; 167:792800

2. Eppel AB: Antidepressants in the treatment of bipolar disor-

der: decoding contradictory evidence and opinion. Harv Rev

Psychiatry 2008: 16:205209

ALAN EPPEL, M.B., F.R.C.P.C.

Hamilton, Ontario, Canada

The author reports no financial relationships with commercial

interests.

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