Letters to the Editor
Lamotrigine and Clozapine
for Bipolar Disorder
TO THE EDITOR: Treatment-resistant bipolar disorder can be
one of the most challenging conditions to manage. There is a
need to develop more effective treatment strategies, including complex regimens of combination therapy. Clozapine has
been used to treat bipolar disorder that has been nonresponsive to lithium and anticonvulsant therapy, but it appears to
be less effective in treating the depressed phase of the illness
(1). Lamotrigine has recently been shown to possess efficacy
in the treatment of bipolar depression without increasing the
rate of switching into mania (2, 3). We report here a case of a
patient with bipolar I disorder who was partially responsive to
lithium and divalproex whose treatment was augmented with
lamotrigine and clozapine.
Mr. A, a 46-year-old man with bipolar I disorder, was referred for follow-up care after hospitalization for 7
months for treatment of mania accompanied by grandiose delusions. During hospitalization he was treated with
300 mg/day of quetiapine, 1200 mg/day of lithium (serum
level=1.1 meq/liter), and 2000 mg/day of divalproex (serum level=65 µg/ml). He had previously been unresponsive to adequate trials of carbamazepine, fluoxetine,
nortriptyline, amitriptyline, protriptyline, tranylcypromine, bupropion, methylphenidate, L-thyroxine, risperidone, olanzapine, and cognitive behavior psychodynamic
psychotherapy. Since life charting suggested that Mr. A
was due to cycle into severe depression, lamotrigine therapy was begun and titrated to 150 mg/day over 8 weeks.
His depression disappeared after 21 days of treatment.
After a 5-day period of euthymia Mr. A cycled into mania, which led to the initiation of clozapine treatment,
starting at 25 mg/day and gradually increasing to 450 mg/
day. After augmentation of divalproex and lamotrigine
therapy with clozapine, his mood stabilized. Lithium and
quetiapine treatment were then gradually discontinued.
Previous side effects, which included tremors, weight
gain, and listlessness, subsided with the discontinuation
of lithium. After 5 months of treatment Mr. A elected to
decrease his dose of clozapine to 200 mg/day because of
excessive daytime fatigue; he subsequently relapsed into
a mild 2-month depression that disappeared after clozapine therapy was resumed. Adjunctive methylphenidate,
20 mg b.i.d., was used to manage his persistent fatigue.
Despite the side effects of excessive salivation and daytime fatigue, he has tolerated the combination of divalproex, lamotrigine, and clozapine and remained without
symptoms of mania for 7 months, after a 34-year history
of periodic mania and a 10-year history of continuous circular cycling.
This case suggests that complex regimens of combination
therapy can be safe and effective in the treatment of patients
with complex, lifelong histories of treatment-resistant bipolar
I disorder. The use of divalproex, lamotrigine, and clozapine
in this patient was reasonably well tolerated. Controlled trials
are needed to more definitely explore the safety and efficacy
of combination therapy in the treatment of bipolar disorder.
Am J Psychiatry 157:9, September 2000
References
1. Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ,
Thompson PA, Meltzer HY: Clozapine for treatment-refractory
mania. Am J Psychiatry 1996; 153:759–764
2. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E,
Rudd GD: A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.
Lamictal 602 Study Group. J Clin Psychiatry 1999; 60:79–88
3. Calabrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J,
Keck PE Jr, Rhodes L, Bolden-Watson C, Zhou J, Ascher JA: Spectrum of activity of lamotrigine in treatment-refractory bipolar
disorder. Am J Psychiatry 1999; 156:1019–1023
JOSEPH R. CALABRESE, M.D.
PRASHANT GAJWANI, M.D.
Cleveland, Ohio
Paroxetine and Irritable Bowel Syndrome
TO THE EDITOR: Treatment with selective serotonin reuptake
inhibitors has been associated with gastrointestinal side effects, including exacerbation of irritable bowel syndrome (1).
In contrast, we describe apparent improvement of irritable
bowel syndrome correlating with paroxetine treatment and
independent of antidepressant response.
Mr. A was 44 years old when he saw his primary care
physician for cramping abdominal pain, excessive flatus,
frequent diarrhea, and an inability to gain weight (6 feet,
155 lb). These symptoms, present for 30 years, had intensified over 1 year with increased stress. A colonoscopy
with a biopsy revealed mild active colitis. Treatment with
mesalamine, 800 mg t.i.d., for 9 weeks was not beneficial. Irritable bowel syndrome was diagnosed, and treatment with dicyclomine, 10 mg t.i.d., for 17 weeks was
unsuccessful.
At a psychiatric evaluation Mr. A complained of gastrointestinal symptoms, low back pain, and recent stress.
He met the criteria for major depressive disorder of moderate severity. Psychotherapy was initiated, and paroxetine, 10 mg/day, was given for 2 weeks, increased to 20
mg/day for 3 weeks, then increased to 30 mg/day. After 2
weeks at 20 mg/day the irritable bowel symptoms fully
disappeared, and Mr. A’s depression was partially relieved.
His depressive symptoms completely disappeared only after 2 weeks at the 30-mg/day dose.
After 1 year of treatment with paroxetine, 30 mg/day,
and with his irritable bowel syndrome and depressive
symptoms in remission, Mr. A’s paroxetine therapy was tapered over 3 months. At 5 mg/day he experienced a relapse of postprandial indigestion and loose stools (two to
four per day). One week after he discontinued paroxetine,
his typical crampy abdominal pain and diarrhea returned,
without a relapse of the depression. These symptoms remitted when Mr. A restarted paroxetine, 30 mg/day. He remained asymptomatic for the next 14 months. Then a second slow taper was attempted. At 10 mg/day the irritable
bowel symptoms returned, without depression. Maintenance therapy at 20 mg/day has controlled his irritable
bowel syndrome symptoms for the past 6 months, and he
has reached his highest weight ever, 167 lb.
The patient’s irritable bowel syndrome disappeared with
paroxetine treatment and twice returned when the dose was
reduced. The slow taper of paroxetine makes it unlikely that
1523
LETTERS TO THE EDITOR
the relapses were actually withdrawal symptoms. The mechanism by which paroxetine may improve irritable bowel syndrome is unclear. On the basis of in vitro studies, paroxetine
has been found to have anticholinergic effects that might improve bowel symptoms, but clinically, this effect appears
minimal (2). For this patient, treatment with an anticholinergic agent, dicyclomine, was ineffective, which raises the
possibility that paroxetine may have improved his irritable
bowel syndrome by means of a serotonergic mechanism. To
our knowledge, there are only two other reports of irritable
bowel syndrome improving with serotonergic antidepressant
treatment (3, 4).
References
1. Efremova I, Asnis G: Antidepressants in depressed patients with
irritable bowel syndrome (letter). Am J Psychiatry 1998; 155:
1627–1628
2. Pollock BG, Mulsant BH, Nebes R, Kirschner MA, Begley AE, Mazumdar S, Reynolds CF III: Serum anticholinergicity in elderly
depressed patients treated with paroxetine or nortriptyline.
Am J Psychiatry 1998; 155:1110–1112
3. Emmanuel NP, Lydiard RB, Crawford M: Treatment of irritable
bowel syndrome with fluvoxamine (letter). Am J Psychiatry
1997; 154:711–712
4. Clouse RE, Lustman PJ, Geisman RA, Alpers DH: Antidepressant
therapy in 138 patients with irritable bowel syndrome: a fiveyear clinical experience. Aliment Pharmacol Ther 1994; 8:409–
416
MICHAEL A. KIRSCH, M.D.
ALAN K. LOUIE, M.D.
San Francisco, Calif.
Nonconvulsive Status Epilepticus After ECT
TO THE EDITOR: Nonconvulsive status epilepticus after ECT is
a rare complication that has been reported in the literature
(1–6). We report a case that developed after an index ECT
treatment.
Ms. A, an 87-year-old woman, was admitted to a geriatric psychiatry unit with a diagnosis of delirium due to a
urinary tract infection. She had a history of major depression and was maintained with desipramine, 50 mg b.i.d.,
and sertraline, 100 mg/day. The urinary tract infection
was treated with trimethoprim/sulfamethoxazole, 160/
800 mg b.i.d., for 5 days. The delirium precipitated a major depressive episode, and Ms. A was referred for ECT. A
computed tomography scan of her head revealed moderate cerebral atrophy and minor periventricular deep
white matter disease but no focal lesions.
The first ECT treatment, delivered in the right unilateral
configuration, lasted 75 seconds. Fifteen minutes after the
procedure ended Ms. A had a generalized tonic-clonic seizure that was terminated with methohexital, 60 mg i.v.
Once the seizure ended, she became more alert.
On the psychiatry unit Ms. A was obtunded and had
slight clonic movements of the left side of her face.
Lorazepam, 2 mg i.v., was administered and followed by
loading with phenytoin, 1.4 mg i.v. An EEG revealed no
normal background activity and almost continuous electrographic seizures over the right hemisphere of the
brain. Ms. A was transferred to the intensive care unit,
where repeat EEGs showed no signs of ictal activity. The
neurology service felt that further ECT was not an option
given the focality of her seizure. Ms. A was discharged to a
nursing home, where she was eventually lost to follow-up.
1524
A MEDLINE search for nonconvulsive status epilepticus revealed six articles involving five patients (1–6). Including our
own patient, three of these were 70 years of age and older (1,
3, 5) and three received ECT in the right unilateral position (1–
3). All cases were identified after changes in mental status after ECT. Two of the patients completed multiple treatments
before developing post-ECT nonconvulsive seizures (2–4).
Ours was the only patient with localizing findings on EEG.
Further treatments have been performed on some of these
patients without recurrence of posttreatment seizures (1, 3,
5). A retrial of ECT for our patient was discussed; however, because of the focality of the seizures, this was not pursued.
We present this case as an unexpected event developing after a first ECT treatment. Further research into possible predictive factors for unexpected post-ECT seizures is needed.
References
1. Crider BA, Hansen-Grant S: Nonconvulsive status epilepticus as
a cause for delayed emergence after electroconvulsive therapy.
Anesthesiology 1995; 82:591–593
2. Grogan R, Wagner DR, Sullivan T, Labar D: Generalized nonconvulsive status epilepticus after electroconvulsive therapy. Convuls Ther 1995; 11:51–56
3. Hansen-Grant S, Tandon R, Maixner D, DeQuardo JR, Mahapatra S: Subclinical status epilepticus following ECT. Convuls
Ther 1995; 11:134–138
4. Rao KMH, Gangadhar BN, Janakiramaiah N: Nonconvulsive
status epilepticus after the ninth convulsive therapy. Convuls
Ther 1993; 9:128–129
5. Solomons K, Holliday S, Illing M: Non-convulsive status epilepticus complicating electroconvulsive therapy (letter). Int J Geriatr Psychiatry 1998; 13:731–734
6. Varma NK, Lee SI: Nonconvulsive status epilepticus following
electroconvulsive therapy. Neurology 1992; 42:263–264
KEVIN SMITH, M.D.
GEORGE KEEPERS, M.D.
Portland, Ore.
Cyproheptadine
for Posttraumatic Nightmares
TO THE EDITOR: Several selective serotonin reuptake inhibitors,
tricyclic antidepressants, benzodiazepines, and monoamine
oxidase inhibitors have been prescribed to treat recurrent
posttraumatic nightmares, but no overwhelming results have
been reported (1). A few authors have suggested that cyproheptadine, a serotonin 2 (5-HT2) antagonist with antihistaminic properties, might be an interesting alternative treatment (2–4). We describe here the effects of cyproheptadine on
EEG sleep measures and its serum level after successful treatment. We have no knowledge of any earlier reports on EEG
data or therapeutic serum levels of cyproheptadine.
Ms. A was a 29-year-old West African asylum seeker who
fled to the Netherlands after having been raped and
nearly killed by rebels. She fully met the DSM-IV criteria
for posttraumatic stress disorder. She had severe nightmares about the rape up to 5 nights a week.
A drug-free standard night polysomnography was performed. Sleep latency was 15 minutes. The first REM period (lasting 9 minutes) occurred 85 minutes after the onset of sleep. After 77 minutes of stage 2 sleep with a cyclic
alternating sleep pattern, a second REM period was recorded (58 minutes). A third REM period (24 minutes) ap-
Am J Psychiatry 157:9, September 2000
LETTERS TO THE EDITOR
peared after 18 minutes of slow-wave sleep. Consecutively, a 56-minute cyclic alternating sleep pattern was
recorded, interrupted by many short arousals and followed by a fourth REM period. After 12 minutes Ms. A
woke up in panic from her “usual nightmare.” At that time
no signs of sleep paralysis or EEG abnormalities were
present on polysomnography.
Despite considerable improvement after psychotherapy, Ms. A’s nightmares continued. Cyproheptadine therapy was prescribed at up to 12 mg at 10:00 p.m. Her
nightmares soon became less frightful, and they decreased to less than one a week. Her serum level of cyproheptadine 12 hours after intake of 12 mg was 6 µg/liter. A
second polysomnography was conducted. Sleep latency
was 10 minutes. Non-REM stage 2 and slow-wave sleep
were interrupted by three arousals. The first REM period
(13 minutes) occurred after 144 minutes of sleep, followed
by slow-wave sleep with two periods showing a cyclic alternating sleep pattern. After 70 minutes REM sleep reappeared for 6 minutes. A final REM period lasted for 10
minutes after a light 5-minute sleep. No nightmares were
reported.
The main differences between the two sleep recordings
were the paucity of deep sleep during the first night and
the percentages of REM sleep—30.4% and 12.6%, respectively (normal values=20%–25%) (5). Moreover, during the
first polysomnography, REM sleep appeared earlier and
more predominantly in the middle third of the night. The
second polysomnography showed a nearly normal sleep
architecture.
In accordance with earlier reports, it seems that cyproheptadine might be of considerable value in the treatment of
posttraumatic nightmares.
References
1. Friedman MJ: Drug treatment for PTSD: answers and questions. Ann NY Acad Sci 1997; 821:359–371
2. Harsch HH: Cyproheptadine for recurrent nightmares (letter).
Am J Psychiatry 1986; 143:1491–1492
3. Brophy MH: Cyproheptadine for combat nightmares in posttraumatic stress disorder and dream anxiety disorder. Mil Med
1991; 156:100–101
4. Gupta S, Austin R, Cali LA, Bhatara V: Nightmares treated with
cyproheptadine (letter). J Am Acad Child Adolesc Psychiatry
1998; 37:570–571
5. Chokroverty S: An overview of sleep, in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, 2nd ed. Edited by Chokroverty S. Boston, ButterworthHeinemann, 1999, pp 7–20
RONALD J.P. RIJNDERS, M.D.
DAVID M. LAMAN, M.D.
HANS VAN DIUJN, M.D., PH.D.
Noordijkerhout, the Netherlands
crease stages of slow-wave sleep without altering total sleep
time (3) and improve sleep outcome (4).
We conducted a double-blind, randomized, placebo-controlled trial of cyproheptadine for treating sleep problems
found in PTSD. The participants were male Vietnam veterans
who had current combat-related PTSD according to the Clinician Administered PTSD Scale (5) and who also reported at
least moderately severe nightmares on the Pittsburgh Sleep
Quality Index (6). The exclusion criteria included current substance abuse, use of a selective serotonin reuptake inhibitor,
mania or hypomania, and any medical condition that contraindicated the use of cyproheptadine. After complete description of the study to subjects, written informed consent
was obtained. Sixty-nine subjects were enrolled in this 2-week
trial across two sites. Posttreatment data on the Clinician Administered PTSD Scale, the Pittsburgh Sleep Quality Index,
and a nightmare questionnaire were available for 60 subjects.
The drug and placebo groups did not differ at pretreatment
on severity scores on the Clinician Administered PTSD Scale
(F=2.06, df=1, 56, p=0.16), total scores on the Pittsburgh Sleep
Quality Index (F≈0.00, df=1, 56, p≈1.00), or nightmare severity
(F=2.80, df=1, 56, p=0.10). When adjusted for pretreatment
scores by analysis of covariance, posttreatment scores on the
Clinician Administered PTSD Scale (F=0.06, df=1, 55, d=0.14,
p=0.81) and scores for nightmare severity (F=1.92, df=1, 55, d=
0.37, p=0.17) were nonsignificantly higher (worse) in the
treatment group than in the placebo group, and scores on the
Pittsburgh Sleep Quality Index showed marginally poorer
sleep in the treatment group than in the placebo group (F=
3.68, df=1, 55, d=0.58, p=0.06). Cyproheptadine serum levels
(determined by gas chromatography/mass spectrometry)
were available at one site for 14 of 15 treated subjects. Partial
correlation analysis, controlling for pretreatment scores,
showed a marginally significant correlation of higher cyproheptadine levels with a worsening of Pittsburgh Sleep Quality
Index scores (r=0.47, p=0.051) but no significant correlation
with scores on the Clinician Administered PTSD Scale (r=0.21,
p=0.25) or scores for nightmare severity (r=0.24, p=0.22) (in
one-tailed tests).
Contrary to expectation (1, 2), cyproheptadine does not appear to be an effective treatment for sleep problems or combat-related PTSD and may even exacerbate sleep disturbance. Although the study group was relatively small, low
power is an unlikely explanation for our nonsignificant findings because of the trend for poorer sleep in the treatment
group and the likely correlation of cyproheptadine levels with
worsening of sleep. Our results reinforce the need for skepticism about open-label or anecdotal findings and for careful
scientific trials to replicate uncontrolled studies.
References
Posttraumatic Stress Disorder
and Sleep Difficulty
TO THE EDITOR: Patients with posttraumatic stress disorder
(PTSD) frequently report difficulty falling asleep, decreased
sleep duration, and trauma-related nightmares. Effective
pharmacotherapeutic treatments for these problems have
not been identified. Open-label trials suggest that cyproheptadine may be a promising treatment (1, 2). Cyproheptadine
acts as a histamine 1 (H1) and serotonin 2 (5-HT2) receptor
antagonist. Evidence indicates that 5-HT2 antagonists inAm J Psychiatry 157:9, September 2000
1. Brophy MH: Cyproheptadine for combat nightmares in posttraumatic stress disorder and dream anxiety disorder. Mil Med
1991; 156:100–101
2. Harsch HH: Cyproheptadine for recurrent nightmares (letter).
Am J Psychiatry 1986; 143:1491–1492
3. Idzikowski C, Mills F, Glennard R: 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Brain Res 1986;
378:164–168
4. Adam K, Oswald I: Effects of repeated ritanserin on middleaged poor sleepers. Psychopharmacology (Berl) 1989; 99:219–
221
1525
LETTERS TO THE EDITOR
5. Blake DD, Weathers F, Nagy LM, Kaloupek DG, Klauminzer G,
Charney DS, Keane TM: The development of a clinician-administered PTSD scale. J Trauma Stress 1995; 8:75–90
6. Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ: The
Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28:193–213
SCOTT JACOBS-REBHUN, M.D.
PAULA P. SCHNURR, PH.D.
MATTHEW J. FRIEDMAN, M.D., PH.D.
ROBERT PECK, M.D.
MICHAEL BROPHY, M.D.
DWAIN FULLER, B.S.
White River Junction, Vt.
Weight Gain With Anorexia Nervosa
TO THE EDITOR: Because of limitations in treatment resources,
patients with anorexia nervosa are often asked to gain weight
in intensive outpatient programs rather than in traditional inpatient treatment settings. Little is known about the efficacy
of intensive outpatient treatment for weight gain in patients
with anorexia nervosa.
Using a retrospective chart review of patients with anorexia nervosa, we matched 23 inpatients and 23 patients in intensive outpatient treatment by diagnosis and age, comparing admission and discharge weights, lengths of stay, and
rates of weight gain. The inpatient and outpatient groups did
not differ significantly on age, age at onset of eating disorder,
or duration of illness. The inpatient group weighed significantly less at admission than the outpatient group (mean
percent of ideal body weight=71%, SD=9, versus mean=80%,
SD=6) (t=–4.0, df=44, p<0.0001). However, the inpatients
gained 15% of their ideal body weight during 46 days (SD=27)
of hospitalization, at a rate of 0.3% of ideal body weight per
day. By comparison, the patients in intensive outpatient treatment gained only 1.4% of ideal body weight during 69 days
(SD=45) of treatment, at a rate of 0.01% of ideal body weight
per day (difference in weight gain: t=5.9, df=44, p<0.0001).
There was a linear relationship between weight gain and
length of stay for the inpatients (r=0.77, p=0.0001) but not for
the outpatients (r=–0.07, n.s.). In fact, only seven of the 23
outpatients showed a gain of more than 5% of ideal body
weight during treatment. The remaining 16 outpatients
showed little weight gain or even lost weight during treatment. Moreover, the outpatients who successfully gained
weight all did so at a lower rate than the inpatient group with
the lowest percentage weight gain. The subgroups of outpatients and inpatients who gained weight did not differ significantly from the outpatients and inpatients who did not gain
weight on any pretreatment variable.
In summary, subjects gained significantly more weight at a
faster rate during inpatient treatment than during intensive
outpatient treatment. Intensive outpatient treatment was less
effective in promoting weight gain and thus may be more expensive over time. It is important to note that the inpatients
were supervised during 35 meals a week, whereas the outpatients were supervised for three to 13 meals a week. It is well
known that people with anorexia nervosa are resistant to eating a normal number of calories, not to mention gaining
weight. Underweight patients with eating disorders tend to
eat little during unsupervised meals; this is likely to account
1526
for the large differences in weight gain between the outpatient and inpatient groups.
The patients receiving intensive outpatient treatment who
gained weight did so at a rate similar to that reported by the
Toronto Hospital partial-hospitalization eating disorder programs (1, 2). We are not aware of other studies comparing
weight gain in inpatients and outpatients with anorexia nervosa in intensive treatment. However, a number of clinical
centers have informally reported similar frustration in trying
to promote weight gain in intensive outpatient programs, as
reported on an e-mail chat line of the Academy for Eating
Disorders.
Further research on the efficacy of eating disorder treatment programs in restoring weight in patients with anorexia
nervosa is greatly needed. On the basis of our findings, such
studies are likely to show that, in the long run, inpatient treatment is more cost-effective than intensive outpatient treatment for restoring weight in underweight patients with anorexia nervosa.
References
1. Piran N, Kaplan A, Garfinkel PE: Evaluation of a day hospital
program for eating disorders. Int J Eat Disord 1989; 8:523–532
2. Kaplan AS, Olmsted MP: Partial hospitalization, in Handbook
of Treatment for Eating Disorders, 2nd ed. Edited by Garner
DM, Garfinkel PE. New York, Guilford Press, 1997, pp 354–360
AMY DEEP-SOBOSLAY, M.ED.
LISA M. SEBASTIANI, B.A.
WALTER H. KAYE, M.D.
Pittsburgh, Pa.
Rapid-Cycling Bipolar Disorder in Children
TO THE EDITOR: There has recently been an increase in the
number of reports focusing on pediatric bipolarity. An issue
of current debate is whether there are presentations of this
condition that are unique to youths (1). The retrospective life
charting method (2) has been used to describe the longitudinal history of bipolar disorder in adults. We are not aware of
any published cases that have utilized this technique in
children.
We gave the retrospective life charts to parents of youngsters seen at our institution who met the DSM-IV criteria for
bipolar disorder type I to assess the longitudinal course of pediatric bipolarity. Specifically, we wished to ascertain whether
pediatric bipolar disorder is a cyclic condition. These procedures were approved by the institutional review board of the
University Hospitals of Cleveland. All guardians provided
written informed consent, and all patients provided assent
before participation.
The parents of 10 outpatients who met the full DSM-IV criteria for a lifetime diagnosis of bipolar disorder type I were instructed on how to complete retrospective life charts, and the
parents of each child were given a life chart to complete for
their child. These patients’ mean age was 12.1 years (range=8–
17). Six of these youths were boys. Through the retrospective
life charts, the parents of each child described a cyclic, biphasic course in which periods of both mania and depression
were present. Seven youths experienced rapid cycling.
In the year before assessment, eight patients had continuous cycling. During this time, the mood episodes were too numerous to count in three of these children. The seven other
Am J Psychiatry 157:9, September 2000
LETTERS TO THE EDITOR
patients had an average of 2.1 episodes of depressed mood,
which lasted an average of 2.9 months. These seven youths
also had an average of 2.7 episodes of elated mood, with a
mean length of 3.6 months. When we used the life charting
method’s severity scale of 0–4, in which a score of 0 indicates
no dysfunction and a score of 4 indicates severe dysfunction,
the mean severity of the elevated moods was 1.7, and the
mean severity of the depressed moods was 1.4. Both of these
scores indicate mild to low-moderate symptom severity. It is
likely that these last results reflected the fact that some of the
children were receiving treatment before their assessment.
Overall, these results suggest that children who meet the
DSM-IV criteria for bipolar disorder type I indeed do have a
cyclic, biphasic disorder that is associated with high rates of
rapid and continuous cycling. These findings also suggest
that the life charting method may be a useful tool in studying
the longitudinal course of children and adolescents with bipolar disorder.
References
1. Biederman J, Klein RG, Pine DS, Klein DF: Resolved: mania is
mistaken for ADHD in prepubertal children. J Am Acad Child
Adolesc Psychiatry 1998; 37:1091–1099
2. Roy-Byrne P, Post RM, Uhde TW, Porcu T, Davis D: The longitudinal course of recurrent affective illness: life chart data research from patients at the NIMH. Acta Psychiatr Scand Suppl
1985; 317:5–34
ROBERT L. FINDLING, M.D.
JOSEPH R. CALABRESE, M.D.
Cleveland, Ohio
Markers for Schizophrenia
TO THE EDITOR: As Michael Davidson, M.D., and colleagues (1)
pointed out, identifying individuals premorbidly who will
later develop schizophrenia offers the prospect of early intervention, the hope of a reduced risk of dangerous behaviors
and hospitalization, and the possibility of improved prognosis and better treatment response. The authors presented a
potentially important set of factors that, when combined,
yield high sensitivity, specificity, and positive predictive value
for identifying individuals at high risk for schizophrenia from
a general population.
A serious difficulty in the development of a screening tool
for schizophrenia in the general population is posed by false
positives. Incorrectly identifying an individual as “at risk” may
have adverse consequences, including unwarranted stigmatization, a negative impact on eligibility to obtain health care
insurance or to pursue other opportunities, unnecessary anxiety and worry for the individual and his or her family, and the
avoidance of age-appropriate challenges (2). Caution must
thus be exercised in applying screening methods for a disorder with low incidence, because even with high specificity,
more individuals identified by a screening test as “at risk” will
be false positive than true positive.
This two-by-two table describes a hypothetical general
population of 10,000 individuals. Assume that 1% will develop
schizophrenia and that the screening test for schizophrenia
has a specificity of 99% and a sensitivity of 75%.
In this example, the screening test identified 174 individuals as at risk for illness; 75 (43%) are correctly classified, and
99 (57%) are incorrectly classified. Thus, even with high specAm J Psychiatry 157:9, September 2000
Actual Result
Test Prediction
Will become ill
Will not become ill
Total
Will Become Ill
Will Not Become Ill
Total
75
25
100
99
9,801
9,900
174
9,826
10,000
ificity, more individuals identified by the screening test are
false positive than true positive. Furthermore, as specificity
decreases, the proportion that are false positive rapidly increases. For example, if the specificity were 90%, then the
screening test would identify 1,065 individuals as at risk, 990
(93%) of whom would be false positive. Dr. Davidson and colleagues reported a “validated specificity” of 99.7% for their
screening tool. Sensitivity and specificity are not absolute values but vary with cutoff scores. Measurement error and other
factors make it unlikely that the screening tool would have
perfect or near-perfect specificity when used to screen for
schizophrenia in other populations. Even with near-perfect
specificity (99.7%), the test predicted that 103 individuals
would become ill, of whom 30 individuals (29%) were false
positive.
The authors concluded that the screening tool can predict
predisposition to schizophrenia and “identifies apparently
healthy individuals who will manifest the disease later who
are not prodromal to psychosis.” I suggest that care should be
exercised in applying any screening strategy for schizophrenia to a general population, given the problem posed by false
positives and the potential harm that could result from falsely
identifying a healthy individual as at risk for the devastating
consequences of schizophrenia. Instead, sequential screening strategies may be valuable, where initial screening identifies high-risk individuals who may then participate in more
definitive diagnostic evaluation (3).
References
1. Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z,
Mark M: Behavioral and intellectual markers for schizophrenia
in apparently health male adolescents. Am J Psychiatry 1999;
156:1328–1335
2. Yung AR, McGorry PD: Is pre-psychotic intervention realistic in
schizophrenia and related disorders? Aust NZ J Psychiatry
1997; 31:799–805
3. McGorry PD: “A stitch in time”…: the scope for preventive strategies in early psychosis. Eur Arch Psychiatry Clin Neurosci
1998; 248:22–31
DIANA O. PERKINS, M.D., M.P.H.
Chapel Hill, N.C.
TO THE EDITOR: We read with great interest the article by Dr.
Davidson et al. The methodological procedures and results of
this study are of special interest to our research team as we
have extensively studied predictive markers of this disorder.
Dr. Davidson and colleagues commented that a strength of
the design of their screening tool is the use of both cognitive
and behavioral measures to identify vulnerability for schizophrenia. Gal (1) stated that these screening instruments are
highly reliable and valid predictors of the constructs that they
purport to measure. However, the criterion used in validation
is based on the “soldier’s rank upon his discharge from the
compulsory service period” (1, p. 80). This leaves our research
team concerned about the appropriateness of the use of this
1527
LETTERS TO THE EDITOR
measure in the present study. Although this instrument was
documented to be a valid predictor of rank, we are uncertain
of its utility in predicting IQ. Furthermore, although Dr.
Davidson et al. commented on the similarities between the
subtests of the WAIS and the subtests of their cognitive battery, no psychometric data were provided by Gal establishing
the measures’ convergent validity.
Dr. Davidson and colleagues established a cutoff of the lowest two quintiles in the social functioning scale for accurately
predicting membership in the patient group. These cutoffs
have no apparent statistical or conceptual validity, as the authors failed to indicate whether patients in the second quintile differed statistically from patients falling into the third
quintile. This overlap between the second and third quintiles
for the patient group reduced the sensitivity in predicting behavioral markers for schizophrenia. Moreover, it is unclear
how the authors determined this cutoff and if it is applied to
the other measures in this study. Assuming that Dr. Davidson
et al. applied a similar method in evaluating the other measures, we believe that this application is misleading in identifying subtle predictors of schizophrenia. For example, with
“organizational ability” and “interest in physical activity,” the
extreme rating of “1” robustly distinguishes between groups;
however, in ratings 2–5, the differences are not consistently
evident. It appears that only extremely small differences between these constructs may be useful as markers in predicting vulnerability to developing schizophrenia.
In summary, we agree with Dr. Davidson and colleagues’
conclusion that abnormalities in social functioning, organizational ability, interest in physical activity, individual autonomy, and intellectual functioning can identify individuals
who will manifest schizophrenia in the future. The degree of
overlap between patients and nonpatients and the absence of
psychometric support for the study’s measures reduce the
sensitivity of this model in predicting predisposition to
schizophrenia.
Reference
1. Gal R: The Selection, Classification and Placement Process: A
Portrait of the Israeli Soldier. Westport, Conn, Greenwood
Press, 1986, pp 77–96
ERIC A. STORCH, B.A.
KATHLEEN GALEK, M.A.
JESSICA GHIGLIONE, B.A.
MERAV GUR, B.A.
LOURDES FALCO, J.D.
NELLY ALIA-KLEIN, B.A.
STEPHANIE FAGIN, B.A.
New York, N.Y.
Dr. Davidson and Colleagues Reply
TO THE EDITOR: Dr. Perkins raises an important issue regarding
the prediction of low-prevalence events. Since there is no biological marker specific to schizophrenia and the prevalence of
the disease is low, any screening tool for schizophrenia must
establish extremely high specificity to be applicable to an entire population. Indeed, our proposed screening tool has the
appropriate specificity (99.7%), but this value, as Dr. Perkins
states, may indeed vary in other populations. We would therefore like to underscore the notion that until this tool is validated in other populations, it should be considered a screening tool rather than a diagnostic marker. Individuals with
1528
scores indicating increased risk for future psychosis should be
rescreened periodically, as preliminary data indicate that the
predictive value of this tool becomes greater as the time between testing and the first psychotic episode diminishes (1).
More important, the values of the screening tool can be confirmed unequivocally only in a true prospective study, which
is currently planned.
Mr. Storch and colleagues indicate that there is a high degree of overlap between patients and nonpatients that might
reduce the sensitivity of the model in predicting schizophrenia. The distribution overlap not only reduces sensitivity but
also specificity, which, as already discussed, is a major problem for any screening tool. Matching patients to their nonpatient schoolmates attenuated both the sensitivity and specificity shortcomings. Table 2 in the article presented the overall
distribution of the patients and matched nonpatients and
therefore did not fully demonstrate the ability of the matching
procedure to discern between patients and nonpatients. The
power of the matching procedure is better exemplified in Table 1, where, for example, 24% of the patients had scores falling below the lowest range of their matched nonpatients on
intellectual functioning. Mr. Storch et al. are also concerned
with the validity of the intellectual and behavioral measures.
The intellectual measures were all revised Hebrew versions of
common measures of verbal and nonverbal intelligence (i.e.,
shorter versions, as in the case of Raven’s Progressive Matrices—R, the Otis test of mental ability, or similar tests in a penand-paper format [Arithmetic—R and Similarities—R tests])
(2), and scores on these tests have been shown to be equivalent to scores on IQ tests (Gal, 1986). The behavioral measures
have been described in more detail in a recent article by our
group (1).
Regarding the cutoff values, the behavioral measures had a
normal distribution in the general population, and the lowest
two quintiles therefore represented performance at 1 SD below the mean, a value that seems to be a reasonable cutoff
point between normal and subnormal performance (e.g., in
intellectual performance) and can be easily applied in clinical
settings.
References
1. Rabinowitz J, Reichenberg A, Weiser M, Mark M, Kaplan Z,
Davidson M: Cognitive and behavioural functioning in men
with schizophrenia both before and shortly after first admission to hospital: cross-sectional analysis. Br J Psychiatry 2000;
177:26–32
2. Lezak MD: Neuropsychological Assessment, 3rd ed. New York,
Oxford University Press, 1995
MICHAEL DAVIDSON, M.D.
ABRAHAM REICHENBERG, M.A.
JONATHAN RABINOWITZ, D.S.W.
MARK WEISER, M.D.
ZEEV KAPLAN, M.D.
MORDEHAI MARK, M.D.
Tel Aviv, Israel
Medication or Psychotherapy
for Severe Depression
TO THE EDITOR: Dr. Robert J. DeRubeis and colleagues (1)
should be commended for a thoughtful and well-executed
study examining the relative efficacy of cognitive behavior
therapy and antidepressant medication for treating severely
Am J Psychiatry 157:9, September 2000
LETTERS TO THE EDITOR
depressed adult outpatients. Although questions may exist
regarding the authors’ methodology (i.e., Might random regression models be more appropriate for approaching this
data set? Might methodological differences between the
studies included in the mega-analysis account, at least in
part, for the differences in outcome observed?), their primary finding remains that cognitive behavior therapy appears to fare as well as medication in the acute treatment of
severe depression. We agree entirely with their assertion that
treatment guidelines should not be based on single studies.
A number of important questions, however, remain unanswered. The relative safety of cognitive behavior therapy and
antidepressant medications, as well as their effectiveness in
preventing relapse and recurrence, for example, was not discussed. As important, it was not clear from the data presented whether the improvements in patient functioning
described are clinically significant. As Jacobson and Truax
(2) noted, statistical comparisons of group differences in
outcome provide little information on the variability of response to treatment within the groups or whether the
changes observed are clinically meaningful. It would be interesting to know what percentage of patients within the
medication and cognitive behavior therapy groups demonstrated a normative level of functioning at the conclusion of
treatment or an elimination of their presenting concerns.
This can be defined statistically, and the data appear to be
available. An analysis of the clinical significance of the
improvements observed would be of interest to practicing
clinicians.
treatments appearing less effective than standard comparisons of baseline and posttreatment scores suggest, such a
finding should be accepted cautiously. A return to normal
functioning is a high clinical standard. As Crits-Cristoph (5)
observed, “With aspects of patient care that involve death or
serious illness, even a small treatment effect might be
deemed to be specially important.” This is nowhere more true
than in the treatment of severely depressed adults. With this
in mind, we suggest that the data analyzed by Dr. DeRubeis et
al. (1) may offer new opportunities for empirical inquiry, including examinations of differences in relapse and recurrence
and the clinical significance of therapeutic gains.
Findings suggest that a large percentage of patients receiving psychotherapy or antidepressant medications make reliable, clinically significant improvements (3, 4). Although examinations of data of clinical significance frequently result in
MARK A. REINCEKE, PH.D.
CYNTHIA J. EWELL FOSTER, M.A.
GREGORY M. ROGERS, PH.D.
ROBIN WEILL, PH.D.
Chicago, Ill.
References
1. DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD: Medications versus cognitive behavior therapy for severely depressed outpatients: mega-analysis of four randomized comparisons. Am J
Psychiatry 1999; 156:1007–1013
2. Jacobson N, Truax P: Clinical significance: a statistical approach
to defining meaningful change in psychotherapy research. J
Consult Clin Psychol 1991; 59:12–19
3. Nietzel MT, Russell RL, Hemmings KA, Gretter ML: Clinical significance of psychotherapy for unipolar depression: a meta-analytic approach to social comparison. J Consult Clin Psychol
1987; 55:156–161
4. Ogles B, Lambert M, Sawyer J: Clinical significance of the National Institute of Mental Health Treatment of Depression Collaborative Research Program data. J Consult Clin Psychol 1995;
63:321–326
5. Crits-Christoph P: The efficacy of brief dynamic psychotherapy:
a meta-analysis. Am J Psychiatry 1992; 149:151–158
Reprints of Letters to the Editor are not available.
Am J Psychiatry 157:9, September 2000
1529