Neuroleptic dose reduction in older psychotic patients

SCHIZOPHRENIA RESEARCH ELSEVIER

Schizophrenia Research 27 (1997) 241 248

Neuroleptic dose reduction in older psychotic patients M. Jackuelyn Harris *, Robert K. Heaton, Alice Schalz, Anne Bailey, Thomas L. Patterson Department of Psychiatry, University of California, San Diego, San Diego VA Medieal Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA

Abstract

We conducted a non-randomized, rater-blind study to safely determine the lowest effective neuroleptic dosage in older psychotic patients and to evaluate the clinical, neuropsychological, and psychosocial effects of neuroleptic dosage reduction. Twenty-seven carefully selected patients with schizophrenia and related psychotic disorders over the age of 45 had their dosage tapered by 25% each month to determine their lowest effective dosage. These patients were compared with patients similar in age, gender, and education who were currently off neuroleptics (n = 19) or maintained on neuroleptics (n=22). All groups were followed for 11 months. Over the follow-up period, 29% of patients in the taper group, 8% of neuroleptic-free patients, and 0% of patients in the maintenance group experienced some increase in psychopathology, although there was no significant change in mean PANSS score in any group, and no patient required hospitalization. Patients in the taper group were maintained on approximately 60% of their original neuroleptic dosage after restabilization. Extrapyramidal symptoms continued to improve over time in the taper group. Neuropsychological testing did not change significantly over time except for those in the taper group who experienced a decrease in memory-retention on the Hopkins Verbal Learning Test and a significant improvement in digit vigilance and Stroop Interference Index. Carefully selected middle-aged and elderly psychotic patients can have their neuroleptic medications reduced without a significant change in psychopathology. Extrapyramidal symptoms may continue to improve gradually over time. The impact on cognition functioning needs further investigation. © 1997 Elsevier Science B.V. Keywords." Neuroleptic; Dose reduction; Psychosis

1. Introduction Numerous studies during the past 35 years have established the efficacy of neuroleptics in the treatment of psychotic symptoms in schizophrenia patients and the ability of these medications to prevent relapse (Davis, 1975; Kane, 1989). * Corresponding author. Tel: 619-534-4020; fax: 619-552-7404; e-maih [email protected] 0920-9964/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PH S0920-9964 (97) 00083-2

Therefore, many schizophrenia patients are maintained on neuroleptic medication. Some such patients develop side effects such as tardive dyskinesia (TD). The risk of TD increases with age, and the incidence of TD is five to six times higher in older patients compared with younger adults (Jeste et al., 1995). Increasing numbers of schizophrenia patients are expected to survive into middle and old age, yet comparatively little is known about the long-term course of schizophrenia.

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Reviews of the literature on the course of schizophrenia suggest that approximately one-third of patients either undergo remission or are left with mild symptoms over the long term (Angst, 1988; Cohen, 1990; Harding et al., 1987b,a). The more positive, dramatic symptoms of schizophrenia, such as hallucinations and delusions, seem to lessen in severity with the passage of time (Bleuler, 1978; Tsuang et al., 1979; Ciompi, 1980; Huber et al., 1980; Ciompi, 1987; Harding et al., 1987b,a). The latter studies, with mean follow-up durations of 22-35 years, found that between 46% and 68% of patients had either fully recovered or significantly improved over time (Ruskin and Nyman, 1991). In a recent study of a 3-year follow-up of older schizophrenia patients, negative symptoms were prevalent, moderately severe, and quite stable over time. Heterogeneity of outcome was, however, observed in all of these studies. Many attempts have been made to uncover associations between specific factors and outcome in schizophrenia. A number of patient-related and illness-related factors have been associated with outcome in the literature, but most of these are of little value for predicting the course in a particular patient (Prudo and Blum, 1987). In the absence of methods to predict long-term outcome, the need for continued neuroleptic medication and the potential benefits of reducing medications are empirical topics for studies. This is particularly true in older schizophrenia patients who are at greater risk for chronic debilitating side effects. We reviewed the literature on neuroleptic discontinuation and found 33 studies involving 2424 patients in whom neuroleptics had been withdrawn (Gilbert et al., 1995). All but one of these studies (Ruskin and Nyman, 1991) included patients with a mean age of 51 years or less. The frequency of post-withdrawal of relapse in the total 33 studies ranged from 6-70%. For all studies, the length of time until relapse varied from 2 weeks to 8 months. Predictors of relapse included: younger age (Rassidakis et al., 1970; Zander et al., 1981; Ruskin and Nyman, 1991 ); younger age at onset of schizophrenia (Rassidakis et al., 1970); non-paranoid schizophrenia (Rassidakis et al., 1970); recent psychiatric hospitalization (Ruskin and Nyman, 1991); higher prior neuroleptic dose (Andrews

et al., 1976; Glazer et al., 1989; Ruskin and Nyman, 1991 ); greater severity of baseline psychopathology (Glazer et al., 1989; Ruskin and Nyman, 1991); fewer total months of hospitalization (Zander et ai., 1981; Glazer et al., 1989); lower baseline plasma HVA (Glazer et al., 1989); lower prolactin levels during neuroleptic treatment (Brown and Laughren, 1981); and more rapid rate of dose reduction (Green et al., 1992). In addition, Lieberman et al. (1987) reported that patients with TD relapsed sooner. We are aware of only one study that evaluated relapse in older schizophrenic patients in an ambulatory care setting. In a study of neuroleptic discontinuation in schizophrenia patients with a mean age of 60 (Ruskin and Nyman, 1991), 18 patients over the age of 52 were randomized to haloperidol or placebo and were followed for 6 months. Five of the 10 patients, who were randomized to placebo, relapsed, compared with only one of the eight patients randomized to haloperidol. Interestingly, however, three of the 10 patients randomized to placebo remained stable without medication for 2.5 years. Relapse was associated with a high baseline psychosis score, high prior neuroleptic dose, a relatively recent psychiatric hospitalization, and a younger age. The goal of our study was to evaluate the effects of gradual reduction of neuroleptic dose in carefully selected patients over age 45, diagnosed with chronic schizophrenia or related psychotic disorders. Demographic and clinical characteristics, extrapyramidal symptoms, TD, and neuropsychological performance were assessed to characterize the population in whom the neuroleptic dosage was reduced and to evaluate the impact of dosage reduction on these variables. Comparison groups were comprised of patients who were off neuroleptics and those maintained on neuroleptics. The assignment to these groups was not random, due to ethical reasons (concern about the possibility of psychotic relapse).

2. Methods

Subjects were recruited by the UCSD Clinical Research Center on Psychosis and Antipsychotics

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in Late Life. Patients came from the San Diego Veterans Affairs Medical Center, and University of California, San Diego Medical Center Inpatient and Outpatient Services; San Diego County Mental Health Services; and private physicians. Patients with schizophrenia and related psychotic disorders (i.e., delusional disorder, schizoaffective disorder, psychosis not otherwise specified) who met DSM-III-R or DSM-IV (American Psychiatric Association, 1987, 1994) criteria and were age 45 years and older were selected. All types of schizophrenia, except for catatonic, were included. In addition, all schizophrenia patients, in whom neuroleptic dosage was reduced, met either one of the following DSM-IV classifications for longitudinal course: episodic with interepisode residual symptoms or episodic with no interepisode residual symptoms. All other diagnostic categories, e.g., schizoaffective disorder, also had to be in remission for at least 1 year. Most of the patients were Caucasian and were men. To rule out 'psychotic' disorders due to other neurological or medical conditions, patients with clinical evidence of focal neurologic disorders, history of head injury with a loss of consciousness for over 30 rain, DSM-III-R or DSM-IV diagnosis of dementia, and hospitalization for any chronic medical disorder during the past year were excluded. These exclusion criteria were used in order to ensure that the neuropsychological testing data reflected impairment due to schizophrenia and not morbidity secondary to other neurological and medical disorders. Patients with a history of being a danger to either themselves or others associated with a lack of or insufficient use of neuroleptic medications also were excluded. Patients without a family member, close friend, board-and-care operator or another person that could be contacted regarding the patient's medical status were excluded. Finally, specific concerns with medication reduction or discontinuation expressed by family members, board-and-care staff, treating psychiatrist, or any of the investigators resulted in the patient being excluded from the study. Of the 130 patients screened for the study, 36 patients met the criteria for taper, 33 were included in the neuroleptic-free comparison group, 35 were included in the neuroleptic maintenance group,

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and the remaining 26 were excluded. The 35 patients included in the maintenance group were those who had a history of dangerousness to self or others, or those for whom the family, treating psychiatrist, or one of the primary investigators had a concern about neuroleptic reduction. The 26 subjects excluded from the study had a history of medication noncompliance, or had no significant other to contact regarding the patient's medical status. Therefore, of the 130 patients screened, only 27% were found to be appropriate for medication reduction and consented to the study. Finally, we only assessed the outcomes for those patients who were followed for a minimum period of 11 months, resulting in a final sample of 27 patients in the taper group, 19 patients in the neurolepticfree group, and 22 patients in the maintenance group. The patients in the taper group were evaluated psychiatrically, neuropsychologically, and for quality of well-being. The psychiatric assessments were obtained at baseline and 1 month after the patients had been stabilized on the lowest effective dosage (end-taper) and again after they had been stabilized for at least 6 months from the end of taper time-point (end of stabilization). These evaluations were also done on patients in the neuroleptic-free and neuroleptic maintenance groups. Due to ethical concerns regarding relapse, none of the patients was randomized to the three groups. The following rating scales were used: Positive and Negative Syndrome Scale (PANGS) for schizophrenia ( K a y et al., 1987); Simpson-Angus scale (Simpson and Angus, 1970) for the assessment of extrapyramidal symptoms; Abnormal Involuntary Movement Scale (AIMS) (National Institute of Mental Health, 1976) to judge intensity of TD; Mini-mental State Examination (MMSE) (Folstein et al., 1975) to judge severity of global cognitive impairment; and Quality of Well-being (QWB) scale (Kaplan et al., 1989; Patterson et al., 1996) for quality of life. Inter-rater reliability assessed with Intra-class Correlation Coefficient (ICC) consistently remained > 0.7 during the study. The following neuropsychological measures were obtained: WAIS-R Digit Span (working memory) and Digit Symbol (psychomotor speed)

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(Wechsler, 1981); Stroop Color and Word Test (speed of processing and cognitive flexibility) (Golden, 1978); Grooved Pegboard (psychomotor speed); Digit Vigilance-time and error (attention) (Lewis and Rennick, 1979); and Hopkins Verbal Learning Test (memory) (Brandt, 1991 ). All of the above evaluations were done at baseline, at the end of the taper phase (1 month dosage after the last reduction), and at 6 months after stabilization on the lowest effective dosage.

2.1. Neuroleptic taper Once a patient was found to be appropriate for neuroleptic reduction, he/she was enrolled in a special medication reduction clinic, and followed on a weekly basis by a nurse case manager. Selected patients were assigned to eventual 100% taper (medication withdrawal), and others to eventual 50% taper. (The assignment to a 50% or 100% taper group was non-random and was done by the patient's physician in consultation with at least two psychiatrists, including MJH). The patients were first stabilized on present neuroleptic dosage for at least 6 months before tapering was begun. In order to minimize the effects of neuroleptic withdrawal, the dosage was then reduced by 25% every month until the patients reached either a 50% or 100% endpoint. The 50% or 100% endpoint was determined by agreement among the treating physician, physician investigators, nurse, patient and family. If the patients experienced any prodromal symptoms (i.e., anxiety, insomnia) or increase in psychotic symptoms, the dosage of medication was increased to the previous dosage on which they had been stabilized. For example, if a patient developed insomnia after reduction to 50% of the baseline dosage, his or her dosage was increased to 75% of the baseline dosage. The assessments were repeated 1 month after the lowest effective dosage was determined in the taper group and 6 months thereafter. None of the taper or the neuroleptic-free patients was being treated with anticholinergic medications. Ten percent of the maintenance group received low-dose anticholinergic medication.

2.2. Statistical analysis" The independent variables were group (taper, neuroleptic-free, and neuroleptic maintenance) and time (baseline, end-of-taper, and end-of-stabilization). The dependent variables were clinical and neuropsychological measures. Because the sample sizes were relatively small and some post-baseline data were missing, we adopted the approach of analyzing the group by time interaction effect separately for the baseline versus end-of-taper times and for the baseline versus end-of-stabilization times. For each dependent variable, two 3 x 2 split-plot ANOVAs were run, and a significant group-by-time interaction effect in either ANOVA was followed by (three) tests of two-group contrast by time interaction effects as well as (three) simple effects tests of time for each group. Preceding these analyses on somewhat reduced sample sizes, we compared the full samples on the baseline data using a one-way ANOVA plus multiple-comparison t-tests.

3. Results

The demographic, clinical, and neuropsychological characteristics of the taper group and the two comparison groups are presented in Table 1. There was no significant difference in mean age, education, gender, ethnicity, marital status, living situation, socioeconomic status, or duration of illness among the three groups. There was a significant difference in the age of onset of illness (defined per DSM-III-R or DSM-IV as the onset of prodromal symptoms) with the patients maintained off neuroleptics (neurolepticfree group) having a later age of onset compared with the patients requiring ongoing neuroleptic treatment (maintenance group). There was no significant group difference in baseline psychopathology (total PANSS score), baseline M M S E score, or quality of life measure (QWB score). Not surprisingly, there was a significant difference in daily neuroleptic dosage (mg chlorpromazine equivalent per day), with the maintenance group receiving more medication than the taper group, and both these groups being on more medication

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Table 1 Baseline characteristics and comparisons

Age (years) Education (years) Gender Age of onset of illness (years)" Duration of illness (years) Daily neuroleptic dose in mg chlorpromazine equivalent a Positive and Negative Syndrome Scale total Abnormal Involuntary Movement Scale total" Simpson Angus Scale score Adjusted Quality of Well-being score Mini-mental State Examination total Digit Symbol Scale score Digit Span Scale score Pegboard Dominant Hand score b Pegboard Non-Dominant Hand score b Digit vigilance time (s)" Digit vigilance (errors) Hopkins Learning score Hopkins Retention score Hopkins Discrimination score Stroop Interference index

Neuroleptic Taper Group A

Neuroleptic-free Group B

Neuroleptic Maintenance Group C

(n=27)

(n=19)

(n=22)

61.8 (10.9) 12.9 (2.3)

64.0 (10.5) 13.5 (3.6)

60.8 (10.1) 12.4 (1.9)

35.9 (14.8) 26.2 (15.9) t90.2 (153.6)

42.6 (19.5) 20.6 (17.5) 0.0 (0,0)

27.2 (11.5) 28.1 (12.5) 774.8 (1227.2)

59.5 (18.0)

56.7(13.1)

60.8 (15.3)

6.0 (3.1)

4.1 (2.7)

4.7 (3.3)

A>B,C

19.4 (7.8) 0.55 (0.13) 27.2 (23) 4.1 (1.4) 6.8 (1.8) 137.8 (39.8) 172.7 (79.3) 797.3 (t79.3) 24.1 (23.3) 16.0 (5.6) -O.2 (O.2) 83.3 (15.7) - 5 . 9 (8.2)

17.6 (4.3) 0.6 (.014) 27.5 (2.1) 6.3 (2.!12) 8.0 (3.74) 86.5 (131.50) 99.6 (24.53) 542.8 ( 170.02 ) 12.8 (15.62) 21.6 (6.33) -0.14 (0.34) 91.7 (5.94) --2.6 (7.66)

17.9 (3.9) 0.6 (0.09) 27.3 (2.3) 6.8 (7.60) 8.0 (4.19) 120.7 (64.87) 127 (50.85) 601.3 (156.99) 18.5 (22.24) 18.7 (6.83) - 0 . 2 (0.31) 86.0 ( 13.01 ) - 5 . 2 (8.96)

A>B A>B A>B,C

Significant Group Contrasts (post-hoc comparisons)

B>C C>A>B

ap < 0.05: bp <0.01.

than the neuroleptic-free group. The taper group had a significantly higher score on the AIMS as well as a poorer performance on pegboard and digit vigilance (time) than the two comparison groups. Over the follow-up period, there was at least a minimal increase in psychopathology in 29% of the taper patients, 8% of the neuroleptic-free patients, and 0% of the neuroleptic maintenance patients, although there was no significant change in the mean PANSS scores in any group. An increase in psychopathology was operationally defined as an increase in any clinical symptom considered to be prodromal symptoms or the re-emergence of psychotic symptoms. The primary symptoms noted in the subjects with an increase in psychopathology were paranoid ideation and/or auditory hallucinations (46% of the patients), anxiety (38% of the patients), and insomnia (15% of

the patients). All patients were stabilized within several days with a small increase in neuroleptic dosage over the last dosage on which the patient had been stabilized. N o patients required hospitalization. We were not able to identify any demographic, clinical, or neuropsychological variables that distinguished patients who had an increase in psychopathology from those who did not. The taper group had a significant mean reduction in dosage from baseline to end-of-taper and end-of-stabilization (Table 2). There was no significant change in psychopathology, QWB score, or AIMS score over the follow-up period, but there was a significant change in the score on the Simpson-Angus scale at the time of stabilization with an improvement in extrapyramidal symptoms. There was no significant change in neuropsychological measures except for an improvement in the performance on the Grooved Pegboard dominant-

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Table 2 Neuroleptic Taper Group (n =27): changes from baseline to end of taper and from baseline to end of stabilization

Daily neuroleptic dose in mg chlorpromazine equivalent a Positive and Negative Syndrome Scale total Abnormal Involuntary Movement Scale total Simpson Angus Scale score" Adjusted Quality of Well-being score Mini-mental State Examination score Digit Symbol score (time) Digit Span score (time) Pegboard Dominant Hand score a Pegboard Non-Dominant score a Digit Vigilance Time (s)" Digit Vigilance (errors) Hopkins Learning score Hopkins Retention score a Hopkins Discrimination score a Stroop Interference Index~

Baseline (mean) A

End of Taper (mean) B

Stabilization (mean) C

Significant Group Contrasts (post-hoc comparisons)

190.2 (153.6)

113.3 185.3)

107.5 (87.6)

A>B,C

59.5 (18.0)

56 (15.4)

49.7 (10.7)

6.0 (3.1)

6.3 (3.4)

5.4 (3.4)

19.4 (7.8) 0.55 (0.13) 27.2 (2.0) 4.1 (1.4) 6.8 (1.8) 137.8 (39.8) 172.7 (79.3) 797.3 (179.3) 24.1 (23.3) 16.0 (5.6)

19.2 (7.6) 0,45 (0.06) 27.2 (2.9) 3.9 (1.9) 6.9 (1.3) 121.2 (36.9) 136.2 (38.6) 820.7 (257.5) 18.1 (20.4) 14.8 (6.1)

17.7 (5.7) 0.49 (0.10) 27.9 (1.1) 5.1 (2,2) 7.0 (1.7) 150.7 (76.3) 153.4 (67.9) 632.6 (131.3) 15.4 (15.9) 18.3 (7.2)

-0.2 (0.2) 83.3(15.7)

-0.4 (0.5) 75.7(16.5)

-0.5 (0.3) 83.3(13.0)

- 5 . 9 (8.2)

- 4 . 9 (6.6)

1.8 (14.2)

A>C

A>B A>B A>C

A>C A>B A>C

Up<0.05.

and non-dominant hands at the end of taper, improvement in digit vigilance and Stroop Interference Index, and worsening of performance on the Hopkins memory-retention score after stabilization. There were no significant changes in clinical, motor, or neuropsychological scores over the follow-up period in the neuroleptic-free and neuroleptic maintenance comparison groups.

4. Discussion Neuroleptic reduction did increase the risk of at least a slight worsening of psychopathology in patients with chronic psychotic disorders, but these patients could still be clinically stabilized on a mean dosage approximately 40% lower than their baseline dosage. The increase in psychopathology was mild and could be easily managed on an outpatient basis. We were not able to identify demographic, clinical, or neuropsychological variables that distinguished patients who had an

increase in psychopathology from those who did not. These variables might have been more predictive in a larger, randomized sample. A sample of chronically impaired schizophrenia patients (Inderbitzin et al., 1994) was able to have relatively high doses of fluphenazine deconoate (23 mg every 2 weeks) successfully reduced by 50%. In another study, a group of chronically hospitalized patients was found to do well with a 60% dose reduction (the initial mean chlorpromazine equivalents were 1290+305mg/day and the final dosage was 437+291 mg/day) (Smith, 1994). Both of these studies had patients treated with higher dosages prior to reduction than our taper sample (mean daily dose of 190 mg chlorpromazine equivalent). Gradual dose reduction methods were used in our study as well as in the two studies mentioned above. Initially, reduction in dosage did not result in an improvement in extrapyramidal symptoms, but over time, these symptoms did improve. Severity of TD did not change. A longer longitudinal follow-up and a larger sample size may be required to evaluate the general impact of neuroleptic reduction on TD.

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Seidman et al. (1993) noted modest neuropsychological changes following neuroleptic dose reduction in a small g r o u p o f nonrelapsing older patients with chronic schizophrenia. Similarly, we did not observe m a r k e d cognitive changes following neuroleptic dose reduction. The taper g r o u p did show a significant improvement in digit vigilance (attention) and Stroop Interference Index ( p s y c h o m o t o r speed and cognitive flexibility) from baseline to stabilization. There was also some suggestion of improvement in m o t o r speed (Pegboard n o n - d o m i n a n t h a n d ) with the initial reduction in dosage in the taper group, but this did not continue over time. There was a significant worsening of performance on memory-retention o f newly learned information ( H o p k i n s Verbal learning test) in the taper group. Neuroleptics have been found to improve performance on tests of attention and information processing in schizophrenia patients (Orzak et al., 1967; Spohn et al., 1977; H e a t o n et al., 1994). The improvement in attention seen in our patients over time might have been due to a decrease in anticholinergic effects with a reduction in neuroleptic dosage (since none o f the taper patients was being treated with anticholinergic antiparkinsonian agents). Limitations of this study include relatively small sample sizes, n o n - r a n d o m assignments o f the patients to the three groups, and non-double-blind assessments (only the raters were blind). Also, given the large n u m b e r o f comparisons, there is a possibility o f type I errors. Nonetheless, the findings are potentially important from a clinical therapeutic viewpoint.

5. Conclusions Carefully selected middle-aged and elderly patients with schizophrenia and related psychotic disorders can have their neuroleptic medications reduced by an average 40% without a significant change in psychopathology. Extrapyramidal symptoms m a y continue to improve gradually over time, The impact on cognition functioning needs further investigation.

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.Acknowledgment Parts o f this work were presented at the A n n u a l Meeting of the Society o f Biological Psychiatry (1996, New York). This work was supported, in part, by National Institute for Mental Health grants MH49671, MH45131, MH43693, MH51459, and by the D e p a r t m e n t o f Veterans Affairs. We also want to acknowledge the help o f L o u A n n M c A d a m s , Ph.D. and Dilip V. Jeste, M.D. in the preparation o f this manuscript.

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