Negative Signs and Symptoms Secondary to
Antipsychotics: A Double-Blind, Randomized Trial
of a Single Dose of Placebo, Haloperidol,
and Risperidone in Healthy Volunteers
Juan Francisco Artaloytia, M.D.
Objective: Despite the clinical observa-
tion that antipsychotics can produce neg- Celso Arango, M.D.
ative symptom scales: the Subjective Def- icit Syndrome Scale total score and an an- this action in healthy subjects. The present Adrienne Lahti, M.D.
Javier Sanz, M.D.
Ana Pascual, M.D.
chiatric Rating Scale (BPRS), the SANS, the Method: The authors used a double-
blind, placebo-controlled trial of single Pedro Cubero, M.D.
score, and the analog scale for subjective done (2.5 mg) in normal subjects. Thirty- drowsiness, risperidone but not haloperi- David Prieto, M.Sc.
than placebo on the BPRS and the SANS.
Tomás Palomo, M.D.
after 3–4 hours and subjective negativesymptoms and drowsiness after 24 hours.
Conclusions: Single doses of both halo-
Results: N ei t he r o f t he a ct i ve dru gs
(Am J Psychiatry 2006; 163:488–493)
Since the therapeutic effects of antipsychotics were been applied to address this issue. On one hand, primary first discovered, it has been clear that they produce unde- negative symptoms have been defined as observer-rated sirable as well as target effects, some of which are difficult negative symptoms that cannot be explained by positive to distinguish from the negative symptoms of schizophre- symptoms, depressive symptoms, or antipsychotic-pro- nia (1–5). Motor side effects can mimic negative symp- duced motor extrapyramidal symptoms. Statistical tech- toms, as well as nonmotor type effects, including indiffer- niques have evolved from simpler, correlational, and cova- ence, apathy, and avolition. These effects have been more riant strategies (11–13) to more sophisticated ones, such frequently described in patient self-reports than in obser- as path analysis (8, 9, 14). The unexplained variance is in- vations made by clinicians. These drug-induced side ef- terpreted as a direct treatment effect on primary negative fects are difficult to distinguish from primary or othersources of secondary negative symptoms (6, 7).
symptoms. However, there are also other sources of sec-ondary negative symptoms, and nonmotor effects of an- Both first- and second-generation antipsychotics re- duce negative symptom ratings in schizophrenia. Several tipsychotics could be considered primary negative symp- studies (8, 9) have reported higher efficacy in negative toms. Therefore, to deal with this, some investigators use a symptoms with second-generation antipsychotics than clinically defined and rated condition called the “deficit with haloperidol; however, the differential effect may be syndrome.” To be categorized as such, all known sources lost when low doses of haloperidol are used (10).
of secondary negative symptoms have to be ruled out, and The effect of antipsychotics on primary negative symp- the negative symptoms have to be long-lasting, with a lon- toms is more controversial. Two general approaches have ARTALOYTIA, ARANGO, LAHTI, ET AL.
Negative symptoms are easy to measure in schizophre- way to rate motor extrapyramidal symptoms, in correlation with nia patients but difficult to attribute to a precise source. To dopamine D2 receptor occupancy (25).
clarify these ambiguities, we studied healthy subjects free Observer-Rated Negative Symptoms
of any psychiatric symptoms. We assessed all negative Negative symptoms were assessed with 1) the Brief Psychiatric symptoms in healthy subjects in response to single doses Rating Scale (BPRS) (26) negative symptoms subscale and 2) the of haloperidol or risperidone in a double-blind, placebo- Scale for the Assessment of Negative Symptoms (SANS) (27) alo- controlled trial. We quantified the subjective experiences gia and affect flattening items. Alogia and affective flattening were of treated individuals as well as the observed effects. Ac- selected from the other items because they appear in several fac- cording to our hypothesis, haloperidol would cause the tor analyses in the negative syndrome, and they do not require afull week of observation. Instead of referring to illness during the most negative symptoms as measured by observer-rated interview, because the participants did not have schizophrenia, and subjective measures and placebo the least.
they were asked to talk about their most recent holidays. Both ofthe raters were psychiatrists (J.F.A. and J.S.). Interrater reliability scores (intercorrelation coefficients) for the two raters on thesescales were between 0.80 and 0.92 for each BPRS item, each of thetwo SANS items, and the Simpson-Angus Rating Scale and Barnes Subjects
Rating Scale for Drug-Induced Akathisia total scores. All four in- The subjects were recruited from advertisements placed in the terviews (baseline and after administration of the placebo and Hospital Universitario 12 de Octubre in Madrid and met the fol- the two drugs) were videotaped, and the raters made a consensus lowing criteria: ages 18 to 60 years, no psychiatric disorder ac- rating after watching the taped interviews.
cording to the Structured Clinical Interview for DSM-IV for nor-mal volunteers, not receiving psychotropic drugs, no drug or Subjective Negative Symptoms
alcohol abuse or dependence (except for nicotine), and no other The Subjective Deficit Syndrome Scale was applied (28). This relevant medical condition. The hospital’s ethical committee for scale asks subjects to rate, from 0 to 4, aspects regarding lack of research with humans approved the research protocol. Written energy, blunted affect, and difficulty in or altered thinking, in- informed consent was obtained from all subjects after we fully ex- cluding, “Do you tire easily (complaints about excessive fatigue)?” “Have you lost the ability to feel emotions (apathy)?” “Do youhave problems concentrating (subjective problems with concen- Design
tration)?” An analog scale (29) of subjective negative symptoms A within-subject design was carried out with haloperidol and was also developed based on Huber’s basic symptoms (30) (the risperidone. Each participant was interviewed and rated four scale is available upon request from the first author). Both scales times. The first interview established baseline variables (with handwriting and a videotaped interview). The subsequent threeinterviews were identical and were performed after double-blind Drowsiness
random assignment of the sequence with which placebo, halo- This concept is defined on the basis of Lewander’s consider- peridol, and risperidone were to be administered.
ation of sedation, which distinguishes between a more generalsomnolence effect versus a more lethargic effect (4). An analog Procedure
scale (29) was developed to measure the sedative or somnolent Because of ethical considerations, only single low doses of the effect. These scales present a line with two ends; each end ex- substances were administered in liquid formulations of placebo, presses a specific maximum and minimum for the variable being haloperidol (5 mg), or risperidone (2.5 mg). Water and lemon ex- evaluated. The subject is asked to make a mark on the line repre- tract were added to the substances to ensure double-blind condi- senting how he or she feels. (The scale is available upon request tions (18). The 2.5-mg dose of risperidone was chosen as the from the first author.) This variable was considered a possible equivalent of 5 mg of haloperidol (19, 20).
confounding factor in the rating of observer-rated and self-rated The baseline assessments were repeated at two different time points. The first evaluation (clinician-rated scales) was made atthe time the substances reached their highest plasma level (T Data Analysis
Tmax for haloperidol is 1.7–6.1 hours (21); it is 0.8 hour (SD=0.3) A balanced crossover experimental design was used, with the for risperidone, and 3.2 hours (SD=1.5) for its active metabolite 9- three treatments and six possible sequences of administration to hydroxyrisperidone (22). Therefore, ratings were performed be- address the issue of treatment order. Five individuals were ran- tween 3 and 4 hours after administration for the first assessment.
The second assessment (self-rated scales) was performed 24 Data were analyzed as usual in this type of design with re- hours after administration and assessed cumulative subjective peated-measures analysis of variance (ANOVA) and treatment experiences over the previous 24 hours. The minimum washout and order of administration as fixed factors. The overall null hy- period between administrations was 48 hours based on half-lives pothesis (placebo=haloperidol=risperidone) was tested for each of haloperidol (14.5–36.7 hours) (21), risperidone (mean=2.8 outcome measured by using a continuous variable. If this null hy- hours, SD=0.5), and 9-hydroxyrisperidone (mean=20.5 hours, pothesis was rejected, pairwise tests of the differences between treatments (haloperidol versus placebo, risperidone versus pla-cebo, and risperidone versus haloperidol) were then performed Motor Signs
with Student’s t test with Bonferroni correction. When the out- Parkinsonism and akathisia were evaluated with standardized come was measured with a noncontinuous variable (Barnes Rat- scales: the Simpson-Angus Rating Scale (23) and the Barnes Rat- ing Scale for Drug-Induced Akathisia, the Simpson-Angus Rating ing Scale for Drug-Induced Akathisia (24), respectively. Handwrit- Scale, or the SANS), only pairwise comparisons were made be- ing was evaluated as another variable of motor outcome. De- cause the number of observations was insufficient to guarantee creased handwriting area has been described as a more precise the requirements of the overall test.
TABLE 1. Descriptive Characteristics of 32 Healthy Subjects Given Placebo, Haloperidol, and Risperidone Individually
Barnes Rating Scale for Drug-Induced Akathisia Scale for the Assessment of Negative Symptoms a Negative handwriting values meant larger letters than positive handwriting values.
TABLE 2. Differences Between Treatments in Motor Signs and Negative Symptoms of 32 Healthy Subjects Given Placebo,
Haloperidol, and Risperidone Individuallya

a ANOVA was not applied to the Simpson-Angus Rating Scale or the SANS. No analysis was performed for the Barnes Ratings Scale for Drug- Induced Akathisia because only three patients rated a 1 on this scale (two subjects taking haloperidol and one taking risperidone).
A significance level of 0.05 was established. Some outcomes shown in Table 1 and Table 2. As for motor symptoms, one that might be affected by drowsiness, specifically observer- and subject reported acute buccolingual dystonia 20 hours af- self-rated negative symptoms, were included in the model as co- ter receiving haloperidol. No significant differences were variates. To rule out any possible confounding effect of other epi-demiological variables (gender, age, smoking status, level of edu- detected between drugs for the Simpson-Angus Rating cation, or body mass index), we applied ANOVA and chi-square Scale score or the handwriting area. No analysis was per- tests to be sure that they were not correlated with the sequence of formed for the Barnes Rating Scale for Drug-Induced Akathisia because only three patients rated a 1 on thisscale (two subjects taking haloperidol and one taking ris- peridone). The participants taking risperidone scored sig- Thirty-two subjects entered the study. Thirty subjects nificantly higher on the BPRS negative symptoms sub- completed it; one person dropped out voluntarily, scale than those receiving placebo; likewise, th e whereas another was eliminated after suffering a hypoten- individuals receiving haloperidol or risperidone scored sive episode with risperidone. Of the completer group, 17 significantly higher on the SANS items versus those re- were women and 13 were men; the mean age was 32.4 ceiving placebo. The participants taking haloperidol or years (SD=10.5, range=18–58). Ten of the completers were risperidone scored significantly higher on the two self- smokers. Mean education in years was 17.1 (SD=1.6, rated scales than those receiving placebo (Table 1 and Ta- range=12–18). Body mass index was 24.7 kg/m2 (SD=7.1, ble 2). The subjects scored significantly higher on drowsi- range=18.8–38.1). The variables were homogeneously dis- ness after taking either haloperidol or risperidone versus tributed in the different groups and randomly assigned to those receiving placebo; in a comparison of the two the different sequences of drug administration. No signifi- drugs, they scored higher with risperidone than with ha- cant differences attributable to the order of administra- loperidol (Table 1 and Table 2). After control for drowsi- tion were detected for any of the variables.
ness, only those taking risperidone scored significantly Descriptive characteristics and differences between higher than those receiving placebo on the BPRS and treatments, before and after control for drowsiness, are SANS negative symptom items (Table 2).
toms by different second-generation antipsychotics. Inthese studies, antipsychotic-induced “nonmotor” nega- tive symptoms could have been considered primary nega- tive symptoms. The estimates of effect size for the medica- tion-induced negative symptoms found in the present study could be useful in evaluating findings from pharma- cological trials of agents that target negative symptoms.
Some authors (4) give definitions for unspecific seda- tion (drowsiness) and specific sedation (Rifkin’s akinesia, which we have called negative signs and symptoms sec- ondary to antipsychotics) that clearly differentiate themconceptually. Nonetheless, we find it complicated to dis-tinguish between them in this manner. In fact, in thepresent study, subjective negative symptoms scales couldnot clearly distinguish between drowsiness and negative signs and symptoms secondary to antipsychotics. The in- formation provided by these scales must be questioned until they can distinguish more clearly between these two factors. This idea receives strong support from data fromvarious authors and clinical descriptions. The point is clarified further by Laborit’s description: The patients required less analgesics and, at the same time, had an unusual state of consciousness in that they were readily aroused but seemed uncon- cerned with the environmental situation. (1) and by an unprompted written report by one of our sub- I feel slow but not sleepy. During the interview I feel clumsy, and I want to finish as soon as possible (it’sdifficult for me to explain what is happening to me).
Drowsiness was also used as a possible confounding fac- The results of the current study indicate that single-dose tor in the rating of observer-rated negative symptoms administration of both haloperidol and risperidone pro- scales (BPRS and SANS). Albeit to a lesser degree than the duces negative symptoms in healthy volunteers, accord- “subjective” scales in our study, these scales were also af- ing to both clinician-rated and self-report scales. Neither fected to the point of rendering insignificant the difference of the drugs produced significant motor extrapyramidal between haloperidol and placebo. However, the differ- symptoms, as measured by the Simpson-Angus Rating ences between risperidone and placebo remained signifi- Scale or the handwriting area, based on the findings of this cant. Drowsiness is hardly ever controlled in the statistical single-dose study. Negative symptoms were found in the approaches used to demonstrate the effect of drugs on pri- absence of a detectable motor extrapyramidal compo- mary negative symptoms. Moreover, high doses of benzo- nent. In the case of risperidone, negative symptoms were diazepines can provoke drowsiness, and this factor might also independent of a sedative effect.
be confounded with observer-rated negative symptoms.
Treatment-induced nonmotor negative symptoms are An interpretation of the differences between haloperi- not taken into account in studies in which primary nega- dol and risperidone depends on their equivalent doses.
tive symptoms are defined as observer-rated negative Several studies have suggested that the doses chosen in symptoms that cannot be explained by positive, depres- the present study were equipotential. The 1997 APA guide- sive, and motor symptoms (8, 9, 14). Because our normal lines (19) indicated that a 1–2-mg dose of risperidone comparison subjects lacked any initial psychopathology, equals a 2-mg dose of haloperidol and that haloperidol the drug-induced nature of these symptoms is clear. Thus, may require doses double those of risperidone. Schotte et we can say that the symptoms are “nonmotor” negative al. (20) measured the occupancy of central neurotransmit- symptoms secondary to antipsychotics. In the studies ter receptors by haloperidol and risperidone in an ex vivo cited (8, 9, 14), unexplained variance is interpreted as a di- quantitative autoradiography. Doses of 0.048 mg/kg of ha- rect treatment effect exerted on primary negative symp- loperidol and 0.11 mg/kg of risperidone were needed to NEGATIVE SYMPTOMS IN HEALTHY SUBJECTS
induce 25% D2 receptor occupancy in the caudate-puta- for research in schizophrenia. Psychiatry Res 1989; 30:119– men. However, other studies have supported equivalent 8. Tollefson GD, Sanger TM: Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-con- Our study group consisted of healthy individuals receiv- trolled clinical trial with olanzapine. Am J Psychiatry 1997; 154: ing single doses of antipsychotics. The effect of antipsy- chotics in patients with schizophrenia may differ from 9. Möller HJ: The negative component in schizophrenia. Acta Psy- that seen in this study with normal comparison subjects.
The study was conducted with a single dose, and the effect 10. Rosenheck R, Perlick D, Bingham S, Liu-Mares W, Collins J, War- ren S, Leslie D, Allan E, Campbell EC, Caroff S, Corwin J, Davis L, of these antipsychotics on the variables assessed could Douyon R, Dunn L, Evans D, Frecska E, Grabowski J, Graeber D, change in chronic settings. Nevertheless, both a review of Herz L, Kwon K, Lawson W, Mena F, Sheikh J, Smelson D, Smith- the literature and clinical experience support the finding Gamble V (Department of Veterans Affairs Cooperative Study that antipsychotics produce negative signs and symptoms Group on the Cost-Effectiveness of Olanzapine): Effectiveness secondary to antipsychotics, not only in healthy subjects and cost of olanzapine and haloperidol in the treatment ofschizophrenia: a randomized controlled trial. JAMA 2003; 290: as shown in the present study but also in schizophrenia patients in long-term treatment. A further limitation was 11. Tandon R, Goldman R, DeQuadro JR, Goldman M, Perez M, Jib- that a benzodiazepine arm was not included, which would son M: Positive and negative symptoms covary during cloza- have made it possible to compare the purer sedative effect pine treatment in schizophrenia. J Psychiatr Res 1993; 27:341– and the neuroleptic effect caused by the antipsychotics.
Drowsiness and subjective negative symptoms were as- 12. Miller D, Arndt S, Andreasen NC: Negative symptoms in anti- psychotic-naive schizophrenics and the effect of haloperidol sessed by self-rated scales 24 hours after drug administra- tion to detect all symptoms that appeared during the en- 13. Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, tire 24-hour period. However, the observer-rated negative Howard A, Kronig M, Bookstein P, Kane JM: Clinical effects of symptoms and motor variables were measured after 3–4 clozapine in chronic schizophrenia: response to treatment hours. Correction for those variables with another variable and predictors of outcome. Am J Psychiatry 1994; 151:1744– evaluated at a later time point could be a potential con- 14. Peralta V, Cuesta MJ, Martinez-Larrea A, Serrano JF: Differenti- founding factor. Finally, the dose chosen might have fa- ating primary from secondary negative symptoms in schizo- vored risperidone versus haloperidol, because although phrenia: a study of neuroleptic-naive patients before and after some reports stated that risperidone is equivalent to halo- treatment. Am J Psychiatry 2000; 157:1461–1466 peridol, we used half the dose of risperidone for compari- 15. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr: A sepa- rate disease within the syndrome of schizophrenia. Arch GenPsychiatry 2001; 58:165–171 16. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Sum- Received Sept. 5, 2004; revisions received Dec. 4, 2004, and May 17, merfelt A, Carpenter WT Jr: Effects of clozapine on positive and 2005; accepted May 27, 2005. From the Hospital Universitario 12 de negative symptoms in outpatients with schizophrenia. Am J Octubre, Madrid; the Department of Psychiatry, Hospital General Uni-versitario Gregorio Marañón; the Maryland Psychiatric Research Cen- ter, University of Maryland School of Medicine, Baltimore; and the De- 17. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr: partment of Health Sciences, Universidad de Alcalá, Madrid. Address Positive and negative symptom response to clozapine in correspondence and reprint requests to Dr. Arango, Departamento schizophrenic patients with and without the deficit syndrome.
de Psiquiatría, Hospital General Universitario Gregorio Marañón, C/ Ibiza, 43, 28009 Madrid, Spain; carango@mce.hggm.es (e-mail).
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Nos. 06-3938, 06-3962, 06-3978, 06-4156, 06-4244 & 06-4257BASF AG,Appeals from the United States District Courtfor the Northern District of Illinois, Eastern Division. No. 04 C 6969— Samuel Der-Yeghiayan , Judge. ARGUED NOVEMBER 30, 2007—DECIDED APRIL 14, 2008Before BAUER, KANNE, and EVANS, Circuit Judges .ŒŒ Following oral argument, Circuit Judge Kenneth F. Rippledisqualified h

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