Treatment of Nonpsychotic Relatives of Patients with
Schizophrenia: Four Case Studies
Ming T. Tsuang, William S. Stone, Larry J. Seidman, Stephen V. Faraone,
Suzanna Zimmet, Joanne Wojcik, James P. Kelleher, and Alan I. Green
Background: Substantial evidence now shows that the
genetic vulnerability to schizophrenia can be manifested
clinically in first-degree relatives of people with schizo-
phrenia, even without the full manifestations of the disor-
der. One pattern of problems observed involves the com-
bination of negative symptoms and neuropsychological
deficits. We have investigated whether a low dose of a
novel antipsychotic medication, risperidone, could atten-
uate these clinical problems in non-psychotic, first-degree
relatives, and report here findings from our first 4 cases.
Methods: Twelve adults who were first-degree relatives of
patients with schizophrenia were evaluated for the pres-
ence of negative symptoms and neuropsychological defi-
cits (in attention and working memory, long-term verbal
memory and executive functions). Four subjects who met
our predetermined criteria, and who did not demonstrate
medical contraindications, were enrolled in a 6-week trial
of risperidone. Clinical and medical measures were as-
sessed before, during and after treatment. Doses of ris-
peridone started at 0.25 mg and were increased to 1.0 –2.0
mg/day.
Results: Three subjects showed substantial reductions in
negative symptoms, and one subject showed modest re-
ductions. All four subjects showed substantial improve-
ments on some tests of attention and working memory.
Side effects of risperidone were temporary and mainly
mild.
Conclusions: These initial findings support two conclu-
sions. First, clinical deficits in non-psychotic first-degree
relatives of people with schizophrenia are identifiable,
and to a significant extent, reversible. Second, risperidone
may eventually serve as an effective treatment for people
whose lives are impaired by similar or related problems.
From the Harvard Medical School Department of Psychiatry at Massachusetts
Mental Health Center (MMHC) and Brockton/West Roxbury VA Medical
Center, Boston, Massachusetts (MTT, WSS, LJS, SVF, SZ, JW, JPK, AIG);
Commonwealth Research Center at MMHC, Boston, Massachusetts (MTT,
WSS, LJS, SVF, SZ, JW, JPK, AIG); Psychiatry Service, Massachusetts
General Hospital, Boston, Massachusetts (MTT, LJS, SVF); Harvard Institute
of Psychiatric Epidemiology and Genetics, Boston, Massachusetts (MTT, LJS,
SVF); and Department of Epidemiology, Harvard School of Public Health,
Boston, Massachusetts (MTT).
Address reprint requests to Ming T. Tsuang, MD, PhD, Harvard Department of
Psychiatry, Massachusetts Mental Health Center, 74 Fenwood Road, Boston,
MA 02115.
Received August 3, 1998; revised October 29, 1998; accepted November 6, 1998.
© 1999 Society of Biological Psychiatry
Biol Psychiatry 1999;45:1412–1418 © 1999 Society of
Biological Psychiatry
Key Words: Schizophrenia, Risperidone, negative symp-
toms, attention, neuropsychology, genetics
Introduction
T here is growing support for the notion that the genetic
liability for schizophrenia could be manifested in
brain dysfunction, even without the full manifestations of
schizophrenia (Faraone et al in press; Meehl 1962; Meehl
1989; Seidman 1997). Evidence now shows that this
liability is characterized clinically by neurologic, psychi-
atric, neuropsychological and psychosocial impairments,
in non-psychotic, first-degree relatives of people with
schizophrenia (e.g., Faraone et al 1999; Green et al 1997b;
Seidman 1997). The psychiatric features in such relatives
often include a preponderance of negative symptoms that
are similar to, but generally milder than, those usually
observed in schizophrenic patients (Tsuang 1993; Tsuang
et al 1991). In contrast, positive symptoms are usually less
evident in biological relatives than they are in those with
schizophrenia or schizotypal personality disorder. The
neuropsychological deficits in relatives frequently involve
impairments in attention, memory and/or selected execu-
tive functions (Faraone et al 1998; Kremen et al 1994),
which are also qualitatively similar to those observed in
patients with schizophrenia and schizotypal personality
disorder (Voglmaier et al 1997).
We recently proposed two reasons to consider treatment
strategies for relatives with negative symptoms and neu-
ropsychological deficits (Faraone et al 1999). First, be-
cause the genetic liability to schizophrenia may be asso-
ciated with clinically meaningful problems that may well
be reversible, its treatment may greatly improve an af-
fected individual’s quality of life. Second, because the
condition may evolve into schizophrenia, the treatment of
such individuals could prevent the onset of schizophrenia
or moderate its course (Green and Schildkraut 1995;
Wyatt 1995).
0006-3223/99/$20.00
PII S0006-3223(98)00364-3
Treatment of Nonpsychotic Relatives
While a number of therapeutic interventions could be
considered, we have speculated about the potential value
of pharmacotherapy, and in particular, the use of novel
antipsychotic medications for such relatives. Trials of
these medications would appear reasonable, since the
pattern of psychiatric and cognitive difficulties they are
intended to treat share etiological and psychopathological
elements with schizophrenia. Trials with the older, typical
antipsychotics were limited by both a reluctance of pa-
tients to use these medications, in part because of their side
effects (Hymowitz et al 1986), and also because of their
limited ability to reduce either negative symptoms (e.g.,
Marder and Meibach 1994) or neuropsychological deficits
(Cassens et al 1990).
Fortunately, the development of novel antipsychotic
medications, such as risperidone, olanzapine and quetiap-
ine have somewhat improved the risk-benefit assessment
for the possible treatment of relatives of patients with
schizophrenia. For example, risperidone, which has been
studied most extensively at this time, reduces positive and
at least some negative symptoms in schizophrenia (Car-
penter et al 1995), and produces fewer extrapyramidal side
effects (at least at lower doses) than do more typical
antipsychotic agents (e.g., Marder and Meibach 1994;
Davis and Janicak, 1996; Rossi et al 1997; Tamminga
1997). Moreover, risperidone improves some cognitive
functions in schizophrenia, at least in chronic populations.
Stip and Lussier (1996), Rossi et al (1997) and Green et al
(1997a) all reported improvement in tests of attention or
working memory. Modest improvements in long term
memory (Stip and Lussier 1996) and executive function
(Rossi et al 1997) were also reported.
Given the relative safety and broad therapeutic efficacy
of risperidone, we have begun a pilot study to assess its
effects in those non-psychotic relatives of patients with
schizophrenia who show a pattern of negative symptoms
and neuropsychological deficits. Our protocol involves
screening first-degree relatives to identify those meeting
our predetermined criteria for these symptoms. Rela-
tives who meet these criteria are then entered into a
brief 6-week trial of low dose risperidone. We report
here data from the first four relatives enrolled in this
pilot, clinical trial.
Methods and Materials
Subjects
Subjects were recruited mainly from a sample of individuals
participating in an ongoing family study of schizophrenia, which
has heretofore focused on the identification of clinical, neuro-
psychological and structural brain abnormalities in first-degree
relatives of people with schizophrenia (e.g., Faraone et al 1995;
Faraone et al 1998; Kremen et al 1994; Seidman et al 1997a;
BIOL PSYCHIATRY 1413
1999;45:1412–1418
Tsuang et al 1991). In the family study, schizophrenic patients
(with DSM-III-R diagnoses; e.g., Seidman et al 1997a) gave
permission for investigators to contact their relatives. Only first
degree relatives of both sexes between ages 19 –50, who spoke
English as a first language, with estimated IQ’s of at least 70
(estimates were derived from age scaled scores of Vocabulary
and Block Design subtests of the Wechsler Adult Intelligence
Scales-Revised), were recruited for the drug study. Exclusion
criteria for relatives included: 1) any lifetime history of psychotic
disorders; 2) substance abuse within 6 months of the study; 3)
head injury with documented loss of consciousness exceeding 5
minutes, or subsequent cognitive deficits; 4) neurologic disease
or damage; 5) medical illness with significant cognitive sequelae;
or 6) history of electroconvulsive treatment. The upper age limit
was chosen to minimize potential side effects of risperidone.
Out of the first 25 subjects who met these criteria, 15 agreed
to further interviews to determine their eligibility to participate in
a medication trial. One subject was excluded because of preg-
nancy, two dropped out before the evaluations were completed,
and one declined to enter the drug study but agreed to a shortened
evaluation. Eleven subjects agreed to an evaluation in which the
presence of negative symptoms and neuropsychological deficits
was assessed.
One subject was also recruited through the Commonwealth
Research Center (CRC) at the Massachusetts Mental Health
Center. Current and former research subjects with DSM-III-R or
DSM-IV diagnoses of schizophrenia were asked permission to
allow us to contact their first-degree relatives for the purpose of
recruiting them for this study. Out of 11 relatives contacted in
this manner, only one provided informed consent for an evalu-
ation of her eligibility for the drug study.
Criteria for Inclusion in a Risperidone Trial
The clinical and neuropsychological impairments required for
eligibility for a risperidone trial were established prior to the trial,
and were based on previous studies of non-psychotic relatives of
people with schizophrenia (Faraone et al 1995). A priori inclu-
sion criteria involved the presence of symptoms or deficits of a
level of at least moderate severity.
CLINICAL CRITERIA. Clinical interviews of relatives were
performed using the Scale for the Assessment of Negative
Symptoms (SANS; Andreasen 1983). For inclusion, subjects had
to have at least 6 items rated as at least moderately impaired (i.e.
ratings of 3 or higher). Seven of the 12 subjects met the clinical
criterion by showing moderate levels of negative symptoms on
the SANS.
NEUROPSYCHOLOGICAL CRITERIA. The neuropsycho-
logical measures included tests of 1) vigilance/working memory,
using the Auditory Continuous Performance Test, with Interfer-
ence (ACPT-INT; Seidman et al 1998; Seidman et al 1997b) and
the Visual CPT, Identical Pairs version (VCPT-IP; Cornblatt et al
1988); 2) verbal memory, using the Logical Memory subtest
from the Wechsler Memory Scale–Revised, and Buschke’s
Selective Reminding Test (SRT); and 3) executive functions,
1414 BIOL PSYCHIATRY
1999;45:1412–1418
using the Delayed Alternation Test and the Object Alternation
Test (Seidman et al 1995).
Moderate or greater deficits (defined as approximately 2 or
more standard deviations below appropriate norms in one do-
main, and at least one standard deviation below average in a
second domain) were required to meet the neuropsychological
criteria. Specific measures of performance were used to evaluate
whether neuropsychological criteria were attained, as follows:
Domain Test Criterion Measure(s)
Attention ™™™™™™™™™3ACPT-INT ™™™™™™™™3Hits in Q3A INT
condition
™™™™™™™™™™™™™3VCPT-IP ™™™™™™™™™™3 Total hits for Digits and
Shapes conditions, D
prime (D1; for Digits
and Shapes
conditions)
Verbal Memory ™™™™3 Logical Memory ™™™™3 Delayed Recall, Savings
scores
™™™™™™™™™™™™™3SRT ™™™™™™™™™™™™™™3 Total Recall, Random
Long Term Retrieval
Executive Function ™3Delayed Alternation™™
3 Total Errors, Whether
training criterion was
met
™™™™™™™™™™™™™3Object Alternation ™™3Total Errors, Whether
training criterion was
met
Deficits in any criterion measure (that equaled or exceeded 2
standard deviations below normal) were accepted as evidence of
at least a moderate deficit in that cognitive domain. Four of the
12 subjects met the criteria for neuropsychological impairment in
at least two domains.
MEDICAL CRITERIA. If subjects met all of the above
criteria, they were then evaluated for medical contraindications
to risperidone treatment. They were also rated for general health
and vital signs. Moreover, electrocardiograms (EKGs) and preg-
nancy tests were obtained, as was blood for a complete blood
count (CBC) with differential, liver function tests, and creatine
phosphokinase (PK) levels. No individuals were excluded be-
cause of medical criteria.
Study Procedures
RECRUITMENT PHASE. The Human Subjects Committee
at the Massachusetts Mental Health Center granted permission to
test 6 subjects, whose results would be reviewed before addi-
tional subjects could be recruited (see Institutional Oversight
section). Subjects were interviewed, rated (with the SANS) and
given neuropsychological tests over a 1–2 day period, 1–2 weeks
before assessment at baseline.
BASELINE PHASE. Those who met the criteria for the
risperidone trial were assessed medically 1–2 days before start-
ing the drug trial.
RISPERIDONE TREATMENT. Risperidone was adminis-
tered for 6 weeks, starting at a dose of 0.25 mg/day. Dosage was
M.T. Tsuang et al
increased gradually by 0.25 mg increments over the first 2 weeks
to a maximum of 2.0 mg/day, unless side effects required the
dosage to be lowered. The dose was chosen to ensure that
subjects had a reasonable chance to respond, but was capped at
2.0 mg to minimize side effects in these subjects. At the
conclusion of treatment, the medication was tapered off over a
3– 4 day period.
ASSESSMENTS DURING TREATMENT. The SANS ratings
were repeated in the baseline phase, and again after 2, 4 and 6
weeks of treatment. After treatment began, subjects returned for
weekly visits to monitor effects of the medication, and to receive
a supply of risperidone for the following week. Vital signs, motor
movements (assessed with the Abnormal Involuntary Movement
Scale, the Simpson-Angus Rating Scale and the Barnes Akathisia
Scale) and other side effects were assessed weekly, and all
medical tests done at recruitment were repeated after week 6.
Portions of the neuropsychological test battery (ACPT-INT and
SRT) were repeated after week 3, and all neuropsychological
tests were repeated after week 6. In all 4 cases, no changes were
observed on the neurological rating scales (i.e., the scales
described above to assess motor movements) over the course of
treatment, and follow-up EKG, CBC, PK and liver function tests
were normal at week 6. No adverse side effects were reported
when risperidone was tapered off after treatment.
Institutional Oversight
All research studies conducted at the Massachusetts Mental
Health Center must receive approval from the Research Com-
mittee, which evaluates proposals for their scientific merit, and
from the Human Subjects Committee (HSC), which evaluates
protocols for ethical concerns related to the use of human
subjects. Both committees granted permission to proceed. Al-
though this study is not the first to administer antipsychotic
medication to non-psychotic research subjects (e.g., Hymowitz et
al 1986), the HSC considered the issue before approving the
project. The investigators worked with the Committee to develop
a new and appropriate protocol that would allow treatment of
individuals with relevant clinical symptoms who do not warrant
a related Axis I diagnosis. Approval was obtained, in part,
because a risk/benefit analysis of administering low doses of
risperidone was favorable, and the stringent entry criteria ensured
that eligible subjects demonstrated at least moderate levels of
clinical symptoms. As part of this process, the investigators
submitted materials related to the study (e.g., telephone and
in-person interview formats) that would demonstrate how they
would approach potential subjects, and how questions asked by
subjects would be answered. For example, it was important to
emphasize that potential subjects were not approached because
the investigators believed they were especially likely to develop
schizophrenia. As a further check, the Committee required
ongoing feedback about our experience with the first 6 subjects
to confirm the safety of our procedures, before permission was
granted to screen additional individuals. Separate consent forms
were used: 1) to obtain permission from CRC subjects to contact
their relatives; and 2) to obtain consent from relatives to enter
the study.
Treatment of Nonpsychotic Relatives
Results
Case Descriptions
Four subjects met our clinical, neuropsychological and
medical criteria required to receive risperidone treatment.
All four cases demonstrated negative symptoms and also
showed deficits in attention and long term verbal memory
[cases 1–3 demonstrated impairments on the Selective
Reminding Test (SRT), a list-learning task, and case 4
demonstrated an abnormally high rate of forgetting on the
Logical Memory Test, which involves retention of narra-
tive prose]; cases 1 and 2 were also impaired in executive
functions. None of these individuals met DSM-IV criteria
for any disorder related to schizophrenia, including schizo-
typal personality disorder. Their case histories are de-
scribed below, along with SANS scores and selected
neuropsychological test scores in cognitive domains that
changed with treatment.
CASE 1. Pretreatment. Ms. S, a 38-year-old di-
vorced female with an estimated IQ of 94, graduated high
school, but with difficulty (e.g., “I don’t understand
math”; “I felt like an idiot”; “I didn’t like to remember
dates”). Overall, Ms. S always felt “like something was
wrong with me.” She has typically held jobs (e.g., clerk)
without a sense of pleasure or fulfillment; she described
her current part-time position as “boring.” She stated she
often avoids social activities because she “prefers to be
alone.” Ms. S was eager to undergo evaluation for the
study, but hoped she would not be excluded from consid-
eration because she thought “I may have Attention Deficit
Disorder.”
Treatment. Ms. S reached a maximum dose of risperi-
done of 1.0 mg/day during week 1, and reported positive
effects of treatment throughout the study. By the end of
week 2, she “enjoyed (social) activities more,” and felt
that her attention and concentration had improved (e.g.,
“things don’t just go by me like they used to,” and “it’s
like I can stop and smell the coffee”). Her total SANS
rating (23 at recruitment; 12 at week 6), number of SANS
items rated moderate or higher (6 at recruitment; 1 at week
6) and neuropsychological test scores in attention (e.g., a
48.6% hit rate on the A-CPT at recruitment; a 67.6% hit
rate at week 6) supported her subjective impressions of the
treatment. Improvements in tests of executive functions
were mild and improvements in tests of memory were
transient. One month after the study ended, Ms. S felt she
had lost the gains she made on the medication—“I was at
one spot and was comfortable”; “I could think things
through from A to B to C, (now) I’m just running in
circles” . . . “I lost something I had.” Ms. S expressed an
interest in finding a way to continue taking risperidone
BIOL PSYCHIATRY 1415
1999;45:1412–1418
after the study concluded, but she did not follow-up an
offer made by the investigators to refer her for treatment.
She reported mild and/or moderate side effects (e.g.,
increased heart rate, weight gain, constipation, muscle
stiffness, headache and tightness in her throat) while
taking risperidone during weeks 1–5, but she had no side
effects in week 6.
CASE 2. Pretreatment. Ms. M, a 33-year-old single
female with an estimated IQ of 92, graduated high school
despite difficulties in “reading and math,” and recently
completed her requirements for a B.A. degree by taking
courses at night. She reported that she works 50 –70
hours/week as a home health aide, and has often worked at
more than one job at a time. Ms. M has been involved
with, but not married to, the father of her 2 children for 14
years. Their relationship has been intermittent, however, in
part because she does not trust him or share her feelings
with him. She described herself as outgoing, but noted that
she “loves to be alone” and “not dependent” on anyone.
Treatment. Ms. M reached a maximum dose of ris-
peridone by the end of week 2, at which time she also
reported feeling calmer (e.g., “not as stressed out getting
from A to B”) and more focused (e.g., “I think things
through more”). By the end of week 3, she reported that
she can now “do things with ease,” and experienced a
greater interest in sex and in socializing outside her home
(e.g., going out to dinner or to a movie). Her children were
“happier,” she said, because “mom isn’t getting upset as
easily.” She noted that she “used to say (and) then think,”
and now she “thinks (and) then says.” Despite these
reported improvements, Ms. M also reported feeling like
her “normal self” during the trial, suggesting that she did
not feel any remarkable effects of the medication. Ms. M’s
subjective impressions of improvement were supported by
reductions in her total SANS scores (25 at recruitment; 12
at week 6), and in the number of SANS items rated
moderate or higher (6 at recruitment; 2 at week 6). Her
impression of feeling more focused was supported by the
neuropsychological test results, particularly in the area of
attention (e.g., a 70.3% hit rate on the A-CPT at recruit-
ment; a 91.9% hit rate at week 6). Like Case 1, Ms. M
showed mild improvements in tests of executive function,
and transient improvements in tests of memory. Over the
course of the study, Ms. M reported mild side effects (e.g.,
increased heart rate, dry mouth, sedation, decreased sexual
interest and constipation) from risperidone intermittently
during weeks 1–3, but no side effects during weeks 4 – 6.
CASE 3. Pretreatment. Mr. R, a 37-year-old single
male with an estimated IQ of 108, dropped out of high
school in the 10th grade, but completed his GED. He
1416 BIOL PSYCHIATRY
1999;45:1412–1418
worked in the family bakery intermittently since the age of
6, but has also held a variety of other jobs for varying
periods of time (e.g., fisherman). He described himself as
a “loner,” but one who “likes to get out and do things”
(e.g., fishing or watching football), sometimes with male
friends. Mr. R ended a 7-year relationship with a girlfriend
before the interview, because they “always fought and
never trusted each other.” He was “not a terribly happy
character” at the time of recruitment, because of difficul-
ties in setting goals and finding satisfying work.
Treatment. Mr. R reached a maximum dose of risperi-
done (2.0 mg/day) by the end of week 2, at which time he
reported feeling calmer, “better rested,” more “enthusias-
tic” and more “positive” than usual, and noted that he
enjoyed spending more time with family members. Mr. R
also reported that his family had noticed a positive change
in him, and felt “proud of (me).” He felt more “focused”
in thinking about employment goals, and during the course
of the study, increased his work hours. Nevertheless, Mr.
R, like Case 2, did not feel any remarkable effects of the
medication, and wondered whether he had been adminis-
tered “a placebo” instead of the risperidone. Mr. R’s
subjective impressions of improvements in his life were
supported by reductions in his total SANS scores (43 at
recruitment; 14 at week 6), SANS scores rated moderate or
higher (7 at recruitment; none at week 6), and by improve-
ments in neuropsychological tests of attention (e.g., a
45.9% hit rate on the A-CPT at recruitment; a 62.7% hit
rate at week 6). Like the first two cases, his most
substantial improvement on a test of long term verbal
memory occurred only transiently. Unlike the other two
cases, however, Mr. R’s performance on the test remained
higher at week 6 than it was at recruitment. More specif-
ically, Cases 1, 2 and 3 all demonstrated a large (2
standard deviations), but transient, improvement on the
SRT. While Cases 1 and 2 declined to their baseline levels
at the end of week 6, however, Case 3 declined only 1
standard deviation, and thus remained 1 standard deviation
above his level at recruitment. Mr. R reported no side
effects from risperidone during weeks 1–2, but did report
increased cigarette craving/smoking (it increased from a
baseline of 11⁄2 packs/day, to about 2 packs/day) during
weeks 3– 6.
CASE 4. Pretreatment. Ms. G, a 43-year-old female
with an estimated IQ of 108, graduated high school, but
experienced difficulties in foreign languages and social
studies, and more generally with attention (“I was always
daydreaming”). She described herself as “painfully shy” as
a child. As an adult, “I can deal with people,” she said,
“but I don’t necessarily choose to. I’d rather be by
myself.” Ms. G works full time as a certified nurse’s aide.
M.T. Tsuang et al
She reported that she does not like her job, but she is
“good at it.” She has been married for 25 years and has
two children, but reported longstanding strains between
her husband and herself (e.g., they “stay out of each other’s
way”). At the time of the study, Ms. G was receiving
fluoxetine (20 mg/day) for symptoms of depression.
Treatment. Ms. G attained a maximum dose of risperi-
done (2.0 mg/day) during the third week, but had her dose
lowered to 0.25 by the end of the study to reduce side
effects. She did not report changes in her mood or in her
social relationships, but she did notice that her “concen-
tration” improved at the end of the study (although she
attributed it more to reductions in side effects than to
effects of treatment). Despite Ms. G’s subjective experi-
ence, moderate reductions were evident in total SANS
scores (29 at recruitment; 21 at week 6), although items
rated moderate or higher showed only a small change (7
such items at recruitment; 6 at week 6). Her impression
that her concentration improved, however, was supported
by a large improvement in auditory attention (a 29.7% hit
rate on the A-CPT at recruitment; a 73.0% hit rate at week
6). Ms. G also showed less forgetting of narrative prose
after treatment (a 66.6% savings score on the Logical
Memory Test at recruitment; a 94.0% savings score at
week 6). In contrast, her performance on tests of visual
attention and verbal memory (i.e., learning and recalling a
list of words) was unchanged. Improvements on tests of
executive function were mild. Over the course of the
study, Ms. G reported mild to moderate side effects
(weight gain, sedation and constipation) that decreased as
her dosage was reduced.
Discussion
These four cases demonstrate that a low dose of risperi-
done given over a 6-week period can have beneficial
effects in non-psychotic, non-schizotypal relatives of pa-
tients with schizophrenia. Three of the four individuals
reported improvements including greater levels of interest
in, and enjoyment of, social activities. Objective measure-
ments also denoted clinically significant reductions in
negative symptoms, particularly in the Anhedonia-Asoci-
ality section of the SANS. Moreover, substantial improve-
ments in attention and working memory were reflected in
neuropsychological tests in all four cases. These gains
appear to be selective and not a function of some gener-
alized effect because not all functions improved; gains in
executive functions were modest, and gains in memory
were temporary. Selective improvement cannot be con-
cluded, however, because psychometric differences be-
tween tasks mitigate against direct comparison of treat-
ment effects (Chapman and Chapman 1978). Moreover,
Treatment of Nonpsychotic Relatives
the possibility that practice effects contributed to improve-
ments on tests of attention cannot be ruled out. Perfor-
mance on the Auditory and Visual CPTs, is, however,
generally stable with repetition (Cornblatt and Keilp,
1994; Seidman et al, 1998). For example, although Seid-
man et al (1998) did find a small, but significant practice
effect on the auditory CPT in normal controls when it was
repeated one day later, the magnitude of the change was
less than 1⁄3 the size of the change demonstrated by cases
1– 4 when the test was repeated several weeks later. We
believe, therefore, that the influence of a practice effect, if
it was operative, was likely to be small compared to the
effect of the treatment.
Two findings were unexpected. First, reasons for the
transient nature of the improvement on verbal memory
(the SRT) were unclear, although risperidone may facili-
tate performance in various cognitive functions at different
optimal doses. Second, Case 4 demonstrated a slightly
different pattern of deficit than did cases 1–3 (e.g., Ms. G
was the only one to show an abnormal rate of forgetting on
the Logical Memory Test). Moreover, although her re-
sponse to risperidone was similar qualitatively to that of
the other cases—i.e., reduced SANS scores and improve-
ment in some measures of attention—she showed a
smaller reduction in SANS scores and described fewer
positive experiences subjectively than did the other indi-
viduals. In light of the relatively similar responses to
risperidone evinced by cases 1–3, the possibility exists that
the combination of fluoxetine with risperidone altered the
outcome of treatment in this individual. In addition, it is
also possible that this subject did not receive a full dose
trial of risperidone (because of side effects produced by
the risperidone-fluoxetine combination), one that might
have resulted in the clinical benefits demonstrated by the
other cases.
The attenuation of clinical symptoms and attentional
dysfunctions by risperidone in these four cases have at
least two important implications. First, it demonstrates that
several key clinical and neuropsychological problems in
non-psychotic, non-schizotypal relatives of patients with
schizophrenia, are reversible, at least in part. And second,
it shows that the impairments in such people may be
ameliorated safely through risperidone treatment. Our
experience with these four relatives raises the possibility
that eventually, risperidone may be an effective treatment
for a population of people whose lives are impaired by
similar or related problems. At this time, however, we
underscore the preliminary and experimental nature of
these findings. For example, we do not yet know whether
risperidone was effective because it counteracted specific
biological deficits in subjects who were genetically related
to patients with schizophrenia, or, because it would have
the same effect in individuals drawn from the general
BIOL PSYCHIATRY 1417
1999;45:1412–1418
population. Moreover, the trial was open, the subjects
were not selected at random, and, as noted above, the
influence of practice effects on improvements in attention
can be assessed only tentatively. Therefore, we do not
recommend using risperidone in this population clinically,
until larger, well-controlled studies determine whether the
implications of our case studies are correct. Such studies to
clarify further the nature, extent and possible remediation
of this pattern of clinical and cognitive deficits, are
currently in progress.
Preparation of this article was supported in part by the National Institute
of Mental Health Grant 1R37MH43518 to Dr. Ming T. Tsuang, a grant
from the Janssen Research Foundation to Drs. Alan I. Green and Ming T.
Tsuang, and the Commonwealth Research Center of the Massachusetts
Department of Mental Health.
We have limited the depth of our case descriptions to improve the
readability of this report. More detailed information, however, is avail-
able from the authors.
References
Andreasen NC (1983): The Scale for the Assessment of Negative
Symptoms (SANS). Iowa City: The University of Iowa.
Carpenter WT, Conley RR, Buchanan RW, Breier A, Tamminga
CA (1995): Patient response and resource management:
another view of clozapine treatment of schizophrenia. Am J
Psychiatry 152:827– 832.
Cassens G, Inglis AK, Appelbaum PS, Gutheil TG (1990):
Neuroleptics: effects on neuropsychological function in
chronic schizophrenic patients. Schizophr Bull 16:477– 499.
Chapman LJ, Chapman JP (1978): The measurement of differ-
ential deficit. J Psychiatric Res 14:303–311.
Cornblatt BA, Keilp JG (1994): Genetics and the pathophysiol-
ogy of schizophrenia. Schizophr Bull 20:31– 46.
Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-
Kimling L (1988): The Continuous Performance Test, Iden-
tical Pairs verstion (CPT-IP): I. New findings about sustained
attention in normal families. Psychiatry Res 26:223–238.
Davis JM, Janicak PG (1996): Risperidone: a new, novel (and
better?) antipsychotic. Psychiatr Ann 26:78 – 87.
Faraone SV, Green AI, Seidman LJ, Tsuang MT (1999): Clinical
implications of schizotaxia: A new direction for research.
Schizophr Bull, in press.
Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ,
Tsuang MT (1995): Neuropsychological functioning among
the nonpsychotic relatives of schizophrenic patients: A diag-
nostic efficiency analysis. J Abnorm Psychol 104:286 –304.
Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR,
Tsuang MT (1998): Neuropsychological functioning among
the nonpsychotic relatives of schizophrenic patients: a four-
year follow-up study. J Abnorm Psychol, in press.
Green AI, Schildkraut JJ (1995): Should clozapine be a first-line
treatment for schizophrenia? The rationale for a double-blind
clinical trial in first-episode patients. Harv Rev Psychiatry
3:1–9.
Green MF, Marshall Jr. BD, Wirshing WC, Ames D, Marder SR,
1418 BIOL PSYCHIATRY
1999;45:1412–1418
McGurk S, et al (1997a): Does risperidone improve verbal
working memory in treatment resistant schizophrenia? Am J
Psychiatry 154:799 – 804.
Green MF, Nuechterlein KH, Breitmeyer B (1997b): Backward
masking performance in unaffected siblings of schizophrenic
patients. Arch Gen Psychiatry 54:465– 472.
Hymowitz P, Frances A, Jacobsberg LB, Sickles M, Hoyt R
(1986): Neuroleptic treatment of schizotypal personality dis-
orders. Compr Psychiatry 27:267–271.
Kremen WS, Seidman LJ, Pepple JR, Lyons MJ, Tsuang MT,
Faraone SV (1994): Neuropsychological risk indicators for
schizophrenia: a review of family studies. Schizophr Bull
20:103–119.
Marder S, Meibach R (1994): Risperidone in the treatment of
schizophrenia. Am J Psychiatry 151:825– 835.
Meehl PE (1962): Schizotaxia, schizotypy, schizophrenia. Am
Psychologist 17:827– 838.
Meehl PE (1989): Schizotaxia revisited. Arch Gen Psychiatry
46:935–944.
Rossi A, Mancini F, Stratta P, Mettei P, Gismondi R, Pozzi F, et
al (1997): Risperidone, negative symptoms and cognitive
deficit in schizophrenia: an open study. Acta Psychiatr Scand
95:40 – 43.
Seidman LJ (1997): Clinical neuroscience and epidemiology in
schizophrenia. Harv Rev Psychiatry 3:338 –342.
Seidman LJ, Breiter H, Goodman JM, Goldstein JM, Woodruff
P, O’Craven K, et al. (1998): A functional magnetic reso-
nance imaging study of auditory vigilance with low and high
information processing demands. Neuropsychology, 12:505–
518.
M.T. Tsuang et al
Seidman LJ, Faraone SV, Goldstein JM, Goodman JM,
Kremen WS, Matsuda G, et al (1997a): Reduced subcor-
tical brain volumes in nonpsychotic siblings of schizo-
phrenic patients: a pilot magnetic resonance imaging study.
Am J Med Gen (Neuropsychiatric Genetics) 74:507–514.
Seidman LJ, Goldstein JM, Breiter HC, Goodman JM, Ward M,
Woodruff P, et al (1997b): Functional MRI of attention in
relatives of schizophrenic patients. Schizophr Res 24:172.
Seidman LJ, Oscar-Berman M, Kalinowski AG, Ajilor O, Kre-
men WS, Faraone SV, et al (1995): Experimental and clinical
neuropsychological measures of prefrontal dysfunction in
schizophrenia. Neuropsychology 9:1–10.
Stip E, Lussier I (1996): The effect of risperidone on cognition in
patients with schizophrenia. Can J Psychiatry 41 (Suppl
2):35S– 40S.
Tamminga CA (1997): The promise of new drugs for schizo-
phrenia treatment. Can J Psychiatry 42:265–273.
Tsuang MT (1993): Genotypes, phenotypes and the brain: a
search for connections in schizophrenia. Br J Psychiatry
163:299 –307.
Tsuang MT, Gilbertson MW, Faraone SV (1991): Genetic
transmission of negative and positive symptoms in the bio-
logical relatives of schizophrenics. In: Marneros A, Tsuang
MT, Andreasen N, editors. Positive vs. Negative Schizophre-
nia. New York: Springer-Verlag, pp 265–291.
Voglmaier MM, Seidman LJ, Salisbury D, McCarley RW
(1997): Neuropsychological dysfunction in schizotypal per-
sonality disorder: a profile analysis. Biol Psychiatry 41:530 –
540.
Wyatt RJ (1995): Early intervention for schizophrenia: can the
course of the illness be altered? Biol Psychiatry 38:1–3.