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Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies
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 schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate 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 presence of negative symptoms and neuropsychological deficits (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 assessed before, during and after treatment. Doses of risperidone 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 reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild. Conclusions: These initial findings support two conclusions. 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 symptoms, 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, psychiatric, 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 executive 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 neuropsychological deficits (Faraone et al 1999). First, because the genetic liability to schizophrenia may be associated with clinically meaningful problems that may well be reversible, its treatment may greatly improve an affected 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 patients 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 quetiapine 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 (Carpenter 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. Relatives 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.
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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 pregnancy, 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 evaluation 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 inclusion 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.
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, neuropsychological 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;
NEUROPSYCHOLOGICAL CRITERIA. The neuropsychological measures included tests of 1) vigilance/working memory, using the Auditory Continuous Performance Test, with Interference (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,
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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 domain, 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 pregnancy 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 because 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 additional 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 starting the drug trial. RISPERIDONE TREATMENT. Risperidone was administered for 6 weeks, starting at a dose of 0.25 mg/day. Dosage was
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 Committee, 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. Although 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 narrative 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 schizotypal personality disorder. Their case histories are described 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 divorced 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 consideration because she thought “I may have Attention Deficit Disorder.”
Treatment. Ms. S reached a maximum dose of risperidone 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
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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 risperidone 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 recruitment; 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
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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 difficulties in setting goals and finding satisfying work. Treatment. Mr. R reached a maximum dose of risperidone (2.0 mg/day) by the end of week 2, at which time he reported feeling calmer, “better rested,” more “enthusiastic” 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 administered “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 improvements 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 specifically, 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.
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 risperidone (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 “concentration” 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 experience, 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 risperidone given over a 6-week period can have beneficial effects in non-psychotic, non-schizotypal relatives of patients with schizophrenia. Three of the four individuals reported improvements including greater levels of interest in, and enjoyment of, social activities. Objective measurements also denoted clinically significant reductions in negative symptoms, particularly in the Anhedonia-Asociality section of the SANS. Moreover, substantial improvements 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 generalized effect because not all functions improved; gains in executive functions were modest, and gains in memory were temporary. Selective improvement cannot be concluded, however, because psychometric differences between tasks mitigate against direct comparison of treatment effects (Chapman and Chapman 1978). Moreover,
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the possibility that practice effects contributed to improvements on tests of attention cannot be ruled out. Performance on the Auditory and Visual CPTs, is, however, generally stable with repetition (Cornblatt and Keilp, 1994; Seidman et al, 1998). For example, although Seidman 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 facilitate 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 response to risperidone was similar qualitatively to that of the other cases—i.e., reduced SANS scores and improvement in some measures of attention—she showed a smaller reduction in SANS scores and described fewer positive experiences subjectively than did the other individuals. 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
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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 available from the authors.
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Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Matsuda G, et al (1997a): Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic 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, Kremen 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 schizophrenia 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 biological relatives of schizophrenics. In: Marneros A, Tsuang MT, Andreasen N, editors. Positive vs. Negative Schizophrenia. New York: Springer-Verlag, pp 265–291. Voglmaier MM, Seidman LJ, Salisbury D, McCarley RW (1997): Neuropsychological dysfunction in schizotypal personality 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.
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 symptoms, 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, psychiatric, 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 executive 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 neuropsychological deficits (Faraone et al 1999). First, because the genetic liability to schizophrenia may be associated with clinically meaningful problems that may well be reversible, its treatment may greatly improve an affected 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 patients 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 quetiapine 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 (Carpenter 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. Relatives 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.
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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 pregnancy, 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 evaluation 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 inclusion 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.
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, neuropsychological 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;
NEUROPSYCHOLOGICAL CRITERIA. The neuropsychological measures included tests of 1) vigilance/working memory, using the Auditory Continuous Performance Test, with Interference (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,
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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 domain, 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 pregnancy 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 because 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 additional 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 starting the drug trial. RISPERIDONE TREATMENT. Risperidone was administered for 6 weeks, starting at a dose of 0.25 mg/day. Dosage was
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 Committee, 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. Although 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 narrative 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 schizotypal personality disorder. Their case histories are described 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 divorced 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 consideration because she thought “I may have Attention Deficit Disorder.”
Treatment. Ms. S reached a maximum dose of risperidone 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
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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 risperidone 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 recruitment; 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
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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 difficulties in setting goals and finding satisfying work. Treatment. Mr. R reached a maximum dose of risperidone (2.0 mg/day) by the end of week 2, at which time he reported feeling calmer, “better rested,” more “enthusiastic” 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 administered “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 improvements 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 specifically, 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.
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 risperidone (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 “concentration” 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 experience, 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 risperidone given over a 6-week period can have beneficial effects in non-psychotic, non-schizotypal relatives of patients with schizophrenia. Three of the four individuals reported improvements including greater levels of interest in, and enjoyment of, social activities. Objective measurements also denoted clinically significant reductions in negative symptoms, particularly in the Anhedonia-Asociality section of the SANS. Moreover, substantial improvements 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 generalized effect because not all functions improved; gains in executive functions were modest, and gains in memory were temporary. Selective improvement cannot be concluded, however, because psychometric differences between tasks mitigate against direct comparison of treatment effects (Chapman and Chapman 1978). Moreover,
Treatment of Nonpsychotic Relatives
the possibility that practice effects contributed to improvements on tests of attention cannot be ruled out. Performance on the Auditory and Visual CPTs, is, however, generally stable with repetition (Cornblatt and Keilp, 1994; Seidman et al, 1998). For example, although Seidman 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 facilitate 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 response to risperidone was similar qualitatively to that of the other cases—i.e., reduced SANS scores and improvement in some measures of attention—she showed a smaller reduction in SANS scores and described fewer positive experiences subjectively than did the other individuals. 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
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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 available from the authors.
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