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Selegiline augmentation of antipsychotics for the treatment of negative symptoms in schizophrenia
Selegiline Augmentation of Antipsychotics for the Treatment of Negative Symptoms in Schizophrenia Sanjay Gupta, Thomas Droney, Alan Kyser, and Peggy Keller This case series describes three patients with a DSM-IV diagnosis of schizophrenia attending a continuing day treatment (CDT) program, They showed significant improvement in negative symptoms and overall func-
tioning after the addition of selegiline to the antipsychotic regimen. No side effects were observed with this combination,
tive in treating the positive symptoms of A schizophrenia such as delusions and hallucinations;
NTIPSYCHOTIC MEDICATIONS are effec-
is maintained via a medication management program, and related groups.
however, their efficacy in treating negative symptoms is limited. Negative symptoms appear early in the course of the illness, are long-standing, are treatment-refractory, and result in an impairment of the quality of life for schizophrenic patients as early as the first year of iUness. 1 In a recent pilot study, Bodkin et al. 2 reported on the efficacy of selegiline augmentation of antipsychotics in the treatment of negative symptoms in patients with schizophrenia and schizoaffective disorder. They found improvement in negative symptoms, as well as depressive symptoms, using selegiline.2 We report on the successful trial of selegiline augmentation of antipsychotics in three patients in the setting of a continuing day treatment (CDT) program. All three patients provided informed consent to a trial of selegiline. In this CDT, all schizophrenic patients are followed clinically using rating scales for which written consent is obtained. The scales used are as follows: Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Simpson-Angus scale, Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Hamilton Rating Scale for Depression (HAM-D). The rating scales were used during follow-up visits (every 3 months) by the treating psychiatrist. All rating scale data presented pertain to symptoms before starting selegiline and at the time of the last assessment by the psychiatrist. A high rate of medication compliance
CASE REPORT
From the SUNY Health Science Center, Syracuse; University of Buffalo, Buffalo; Department of Psychiatry, Olean General Hospital, Olean; and Cattaraugus County Day Treatment Program, Olean, NY. Address reprint requests to Sanjay Gupta, M.D., Research and Education Division of Psychiatric Network, 2221 W State St, Olean, NY 14760. Copyright © 1999 by W.B. Saunders Company 0010-440X/99/4002-0006510.00/0 148
Copyright© 1999by W.B. Saunders Company
Case 1 Mr. P., a 61-year-old man with a 26-year history of chronic disorganized schizophrenia and a resident of a group home has been attending the CDT since May 1994. His positive symptoms of psychosis were controlled on perphenazine 20 mg three times daily augmented with divalproex 500 mg three times daily. He was also being treated with trihexyphenidyl 1 mg twice daily for neuroleptic-induced parkinsonism, He had prominent negative symptoms, which included marked affective flattening, anergia, and avolition. He was a 1.5-pack/d cigarette smoker. He was started on selegiline 5 mg in the morning and at noon in January 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 34; SANS, 61; Simpson-Angus, 6; MMSE, 29; and GDS, 1. Eight months later at the time of this chart review, the ratings showed the following: BPRS, 34; SANS, 45; Simpson-Angus, 4; MMSE, 28; and GDS, 1. In addition, there were anecdotal reports from the staff at the CDT and the group home indicating that his speech was more spontaneous, he initiated tasks of his own volition, and he exhibited a broader range of affect. The time to response was approximately 2 weeks after starting selegiline. Prior to selegiline, he needed recurrent prompting to do his share of chores such as taking out the recyclables each week. On this medication, he performed this chore weekly on his own without any prompting. The patient also reported subjective improvement in his overa/1 functioning. He had been on the same dosage of selegiline for 1 year.
Case 2 Ms. K., a 40-year-old woman with a 12-year history of chronic schizophrenia and a resident of a group home, had attended the CDT since November 1993. Her positive symptoms of psychosis were controlled on risperidone 8 mg at bedtime. She was also receiving sertraline 100 mg daily for depression and clonazepam .5 mg twice daily to reduce anxiety. She had prominent negative symptoms, which included marked affective flattening and anergia. She was a one-pack/d cigarette smoker. Ms. K. was started on selegiline 5 mg in the morning and at noon in April 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 36; SANS, 42; Simpson-Angus, 3; and HAM-D, 9. Three months later at the time of this chart review, the ratings showed the following: BPRS, 33; SANS, 36; Simpson-Angus, 3; and HAM-D, 7. The staff from the group home and CDT reported a wider range for her affect, an increase in spontaneous speech, and an
Comprehensive Psychiatry,Vol. 40, No. 2 (March/April), 1999: pp 148-150
SELEGILINE AUGMENTATION OF ANTIPSYCHOTICS
increase in her ann swing at ambulation. She surprised the staff by saying "hello" with a smile, which was new for her. She reported that she felt better overall. The time to response was approximately 10 days after selegiline was started. No medication side effects or drug interactions were observed. The patient remains on the same dosage of selegiline at the 8-month follow-up study.
Case 3
Ms. D., a 41-year-old woman residing independently in the community with a 23-year history of schizoaffective disorder and posttraumatic stress disorder, had attended the CDT since June 1994. Her positive symptoms of psychosis were controlled on risperidone 4 mg at bedtime. She was also taking paroxetine 20 mg daily for depression and cyproheptadine 8 mg at bedtime for relief of nightmares. She had prominent negative symptoms, which included marked amotivation, affective flattening, and anergia. She was a two-pack/d cigarette smoker. She was started on selegiline 5 mg in the morning and at noon in August 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 26; SANS, 28; Simpson-Angus, 1; and HAM-D, 4. Two months later at the time of this chart review, the ratings showed the following: BPRS, 27; SANS, 20; Simpson-Angus, 1; and HAM-D, 5. The CDT staff reported a noticeable increase in her range of affect, increased motivation, and increased participation in activities outside the program. She reported that she had started playing games with her daughter for the first time. She felt that her overall improvement was mild. The time to response was approximately 1 week after selegiline was started. No medication side effects or drug interactions were observed. The patient remains on the same dosage of selegiline at the 4-month follow-up study. DISCUSSION
All three patients we treated with selegiline had a notable improvement. They were noted to be more animated and social by the psychiatrist, therapist, and other day-treatment staff. They made progress socially and in their capacity for self-care, but not vocationally. However, none of these patients could be discharged to a less intensive level of care. All three patients were on a similar dosage of selegiline, 5 mg in the morning and at noon. No side effects were observed despite the use of other psychotropic medications such as selective seroto-
149
nin reuptake inhibitors. All three patients in our case series had well-controlled positive symptoms, and two had depression that was controlled as reflected by the HAM-D. In this sample, there were no nonresponders using the selegiline augmentation strategy. However, it should be noted that the sample size in this series is small (N = 3). Monoamine oxidase inhibitors (MAOIs) have been reported to activate patients in anergic states. 3 The accidental finding that iproniazid relieved gloom in tuberculosis patients led to its trial in psychiatric patients. 4 It was first tried in schizophrenic patients, and was noted to have an activating effect but no side effects.5 Subsequently, studies using MAOIs in combination with antipsychotics found improvement in negative symptoms associated with schizophrenia; however, there were also reports of exacerbation of psychosis. 4,6,7 Dietary and medication restrictions and the possibility of precipitating psychosis kept MAOI augmentation for treating negative symptoms out of general psychopharmacological practice. 2 The study by Bodkin et al.z and our case series demonstrate that selegiline, a selective irreversible MAO-B inhibitor that oxidizes only dopamine and certain trace monoamine, should be reconsidered as a viable option. Selegiline remains MAO-Bselective at dosages less than 15 mg/d. 8 It was introduced for the treatment of L-dopa-refractory Parkinson's disease. 8 This agent has a low risk of tyramine reaction at dosages less than 15 mg daily. The neurochemical mechanisms underlying negative symptoms are unclear, as there is no definite pathophysiological model. Several mechanisms have been proposed, including dopamine deficiency, cerebral atrophy, noradrenergic excess, early brain injury, and cholinergic hyperactivity.9-15Bowers I6 showed that low CSF homovanillic acid (HVA) was particularly associated with withdrawn and motivationless schizophrenic patients thought to have a poor prognosis. Following this report, Post et al. 17 suggested that the basic schizophrenic defect was associated with decreased dopamine release. This was based on CSF findings showing a reduction in HVA concentrations in patients after recovery from acute symptoms, with those with insidious illness having the lowest HVA in the postacute stage. 17 The improvement of negative symptoms associated with selegiline augmentation supports the hypodopaminergic theory. Selegiline
150
GUPTA ET AL
may be effective by increasing dopaminergic transmission in the prefrontal cortex. A distinct hypokinetic syndrome consisting of slowed motor activity with difficulty initiating and sustaining behaviors, anhedonia with sad mood and reduced affective range, and cognitive impairment has been reported by Bermanzohn and Siris. 18This syndrome of akinesia has been reported to exist across diagnostic categories such as parkinsonism, retarded depression, and the negative symptoms of schizophrenia. 18 In these diagnoses, reduced dopa-
mine turnover in the brain has been hypothesized to play a part in the pathophysiology of each, although controversies exist. All of the patients had anergia, which suggests that the above-mentioned hypothesis is interesting and requires further investigation. The treatment of negative symptoms in chronically ill schizophrenic patients by selegiline augmentation to enhance dopamine function is an intriguing possibility, as suggested by our case series and the study by Bodkin et al. 2 This strategy needs further evaluation using controlled studies.
REFERENCES 1. Gupta S, Andreasen NC, Amdt S, Flaum MA, Hubbard WC, Ziebell S. The Iowa Prospective Longitudinal Study of Recent Onset Psychoses: one year follow-up of first episode subjects. Schizophr Res. 1997;23:1 - 1 3 . 2. Bodkin AJ, Cohen BM, Salomon MS, Cannon SE, Zornberg GL, Cole JO. Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. J Nerv Ment Dis 1996;184:295301. 3. Tyrer R Towards rational therapy with monoamine oxidase inhibitors. Br J Psychiatry 1976;128:354-360. 4. Cole JO, Jones RT, Klerman GL. Drug therapy. Prog Neurol Psychiatry 1961;16:539-574. 5. Kamman GR, Freeman JG, Lucero R. The effect of iproniazid on the behavior of long-term mental patients. J Nerv Ment Dis 1953;118:391-407. 6. Bucci L. The negative symptoms of schizophrenia and the monoamine oxidase inhibitors. Psychopharmacology 1987;91: 104-108. 7. Siris SG, Van Kammen DE Docherty JR The use of antidepressant medication in schizophrenia: a review of the literature. Arch Gen Psychiatry 1978;35:1367-1377. 8. Yu PH, Bouton AA. Clinical pharmacology of MAO-B inhibitors. In: Kennedy SH (ed): Clinical Advances in Monoamine Oxidase Inhibitor Therapies. Washington, DC: American Psychiatric Association, 1994:61-82. 9. Mackay AVR Positive and negative symptoms and the role of dopamine. Br J Psychiatry 1980;137:379-383.
10. Van Kammen DE Van Kammen WB, Mann LS. Dopamine metabolism in the cerebrospinal fluid of drug-free schizophrenic patients with and without cerebral atrophy. Arch Gen Psychiatry 1986;43:978-983. 11. Weinberger D. The implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660-669. 12. Stein L, Wise CD. Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-hydroxydopamine. Science 1971;171:1032-1036. 13. Rosen J, Silk KR, Rice HE, Smith CB. Platelet alpha 2 adrenergic dysfunction in negative symptom schizophrenia: a preliminary study. Biol Psychiatry 1985;20:539-545. 14. Murray RM, Lewis SM, Reveley AM. Towards an etiological classification of schizophrenia. Lancet 1985;1:10231026. 15. Tandon R, Greden JF. Cholinergic hyperactivity and negative schizophrenic symptoms. Arch Gen Psychiatry 1989;46: 745-753. 16. Bowers MB. Central dopamine turnover in schizophrenic syndromes. Arch Gen Psychiatry 1974;31:50-54. 17. Post RM, Fink E, Carpenter WT, Goodwin FF. Cerebrospinal fluid amine metabolites in acute schizophrenia. Arch Gen Psychiatry 1975;32:1063-1069. 18. Bermanzohn PC, Siris SG. Akinesia: a syndrome common to parkinsonism, retarded depression, and negative symptoms of schizophrenia. Compr Psychiatry 1992;33:221-232.
tioning after the addition of selegiline to the antipsychotic regimen. No side effects were observed with this combination,
tive in treating the positive symptoms of A schizophrenia such as delusions and hallucinations;
NTIPSYCHOTIC MEDICATIONS are effec-
is maintained via a medication management program, and related groups.
however, their efficacy in treating negative symptoms is limited. Negative symptoms appear early in the course of the illness, are long-standing, are treatment-refractory, and result in an impairment of the quality of life for schizophrenic patients as early as the first year of iUness. 1 In a recent pilot study, Bodkin et al. 2 reported on the efficacy of selegiline augmentation of antipsychotics in the treatment of negative symptoms in patients with schizophrenia and schizoaffective disorder. They found improvement in negative symptoms, as well as depressive symptoms, using selegiline.2 We report on the successful trial of selegiline augmentation of antipsychotics in three patients in the setting of a continuing day treatment (CDT) program. All three patients provided informed consent to a trial of selegiline. In this CDT, all schizophrenic patients are followed clinically using rating scales for which written consent is obtained. The scales used are as follows: Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Simpson-Angus scale, Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Hamilton Rating Scale for Depression (HAM-D). The rating scales were used during follow-up visits (every 3 months) by the treating psychiatrist. All rating scale data presented pertain to symptoms before starting selegiline and at the time of the last assessment by the psychiatrist. A high rate of medication compliance
CASE REPORT
From the SUNY Health Science Center, Syracuse; University of Buffalo, Buffalo; Department of Psychiatry, Olean General Hospital, Olean; and Cattaraugus County Day Treatment Program, Olean, NY. Address reprint requests to Sanjay Gupta, M.D., Research and Education Division of Psychiatric Network, 2221 W State St, Olean, NY 14760. Copyright © 1999 by W.B. Saunders Company 0010-440X/99/4002-0006510.00/0 148
Copyright© 1999by W.B. Saunders Company
Case 1 Mr. P., a 61-year-old man with a 26-year history of chronic disorganized schizophrenia and a resident of a group home has been attending the CDT since May 1994. His positive symptoms of psychosis were controlled on perphenazine 20 mg three times daily augmented with divalproex 500 mg three times daily. He was also being treated with trihexyphenidyl 1 mg twice daily for neuroleptic-induced parkinsonism, He had prominent negative symptoms, which included marked affective flattening, anergia, and avolition. He was a 1.5-pack/d cigarette smoker. He was started on selegiline 5 mg in the morning and at noon in January 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 34; SANS, 61; Simpson-Angus, 6; MMSE, 29; and GDS, 1. Eight months later at the time of this chart review, the ratings showed the following: BPRS, 34; SANS, 45; Simpson-Angus, 4; MMSE, 28; and GDS, 1. In addition, there were anecdotal reports from the staff at the CDT and the group home indicating that his speech was more spontaneous, he initiated tasks of his own volition, and he exhibited a broader range of affect. The time to response was approximately 2 weeks after starting selegiline. Prior to selegiline, he needed recurrent prompting to do his share of chores such as taking out the recyclables each week. On this medication, he performed this chore weekly on his own without any prompting. The patient also reported subjective improvement in his overa/1 functioning. He had been on the same dosage of selegiline for 1 year.
Case 2 Ms. K., a 40-year-old woman with a 12-year history of chronic schizophrenia and a resident of a group home, had attended the CDT since November 1993. Her positive symptoms of psychosis were controlled on risperidone 8 mg at bedtime. She was also receiving sertraline 100 mg daily for depression and clonazepam .5 mg twice daily to reduce anxiety. She had prominent negative symptoms, which included marked affective flattening and anergia. She was a one-pack/d cigarette smoker. Ms. K. was started on selegiline 5 mg in the morning and at noon in April 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 36; SANS, 42; Simpson-Angus, 3; and HAM-D, 9. Three months later at the time of this chart review, the ratings showed the following: BPRS, 33; SANS, 36; Simpson-Angus, 3; and HAM-D, 7. The staff from the group home and CDT reported a wider range for her affect, an increase in spontaneous speech, and an
Comprehensive Psychiatry,Vol. 40, No. 2 (March/April), 1999: pp 148-150
SELEGILINE AUGMENTATION OF ANTIPSYCHOTICS
increase in her ann swing at ambulation. She surprised the staff by saying "hello" with a smile, which was new for her. She reported that she felt better overall. The time to response was approximately 10 days after selegiline was started. No medication side effects or drug interactions were observed. The patient remains on the same dosage of selegiline at the 8-month follow-up study.
Case 3
Ms. D., a 41-year-old woman residing independently in the community with a 23-year history of schizoaffective disorder and posttraumatic stress disorder, had attended the CDT since June 1994. Her positive symptoms of psychosis were controlled on risperidone 4 mg at bedtime. She was also taking paroxetine 20 mg daily for depression and cyproheptadine 8 mg at bedtime for relief of nightmares. She had prominent negative symptoms, which included marked amotivation, affective flattening, and anergia. She was a two-pack/d cigarette smoker. She was started on selegiline 5 mg in the morning and at noon in August 1997. At the time of starting selegiline, the rating scale scores were as follows: BPRS, 26; SANS, 28; Simpson-Angus, 1; and HAM-D, 4. Two months later at the time of this chart review, the ratings showed the following: BPRS, 27; SANS, 20; Simpson-Angus, 1; and HAM-D, 5. The CDT staff reported a noticeable increase in her range of affect, increased motivation, and increased participation in activities outside the program. She reported that she had started playing games with her daughter for the first time. She felt that her overall improvement was mild. The time to response was approximately 1 week after selegiline was started. No medication side effects or drug interactions were observed. The patient remains on the same dosage of selegiline at the 4-month follow-up study. DISCUSSION
All three patients we treated with selegiline had a notable improvement. They were noted to be more animated and social by the psychiatrist, therapist, and other day-treatment staff. They made progress socially and in their capacity for self-care, but not vocationally. However, none of these patients could be discharged to a less intensive level of care. All three patients were on a similar dosage of selegiline, 5 mg in the morning and at noon. No side effects were observed despite the use of other psychotropic medications such as selective seroto-
149
nin reuptake inhibitors. All three patients in our case series had well-controlled positive symptoms, and two had depression that was controlled as reflected by the HAM-D. In this sample, there were no nonresponders using the selegiline augmentation strategy. However, it should be noted that the sample size in this series is small (N = 3). Monoamine oxidase inhibitors (MAOIs) have been reported to activate patients in anergic states. 3 The accidental finding that iproniazid relieved gloom in tuberculosis patients led to its trial in psychiatric patients. 4 It was first tried in schizophrenic patients, and was noted to have an activating effect but no side effects.5 Subsequently, studies using MAOIs in combination with antipsychotics found improvement in negative symptoms associated with schizophrenia; however, there were also reports of exacerbation of psychosis. 4,6,7 Dietary and medication restrictions and the possibility of precipitating psychosis kept MAOI augmentation for treating negative symptoms out of general psychopharmacological practice. 2 The study by Bodkin et al.z and our case series demonstrate that selegiline, a selective irreversible MAO-B inhibitor that oxidizes only dopamine and certain trace monoamine, should be reconsidered as a viable option. Selegiline remains MAO-Bselective at dosages less than 15 mg/d. 8 It was introduced for the treatment of L-dopa-refractory Parkinson's disease. 8 This agent has a low risk of tyramine reaction at dosages less than 15 mg daily. The neurochemical mechanisms underlying negative symptoms are unclear, as there is no definite pathophysiological model. Several mechanisms have been proposed, including dopamine deficiency, cerebral atrophy, noradrenergic excess, early brain injury, and cholinergic hyperactivity.9-15Bowers I6 showed that low CSF homovanillic acid (HVA) was particularly associated with withdrawn and motivationless schizophrenic patients thought to have a poor prognosis. Following this report, Post et al. 17 suggested that the basic schizophrenic defect was associated with decreased dopamine release. This was based on CSF findings showing a reduction in HVA concentrations in patients after recovery from acute symptoms, with those with insidious illness having the lowest HVA in the postacute stage. 17 The improvement of negative symptoms associated with selegiline augmentation supports the hypodopaminergic theory. Selegiline
150
GUPTA ET AL
may be effective by increasing dopaminergic transmission in the prefrontal cortex. A distinct hypokinetic syndrome consisting of slowed motor activity with difficulty initiating and sustaining behaviors, anhedonia with sad mood and reduced affective range, and cognitive impairment has been reported by Bermanzohn and Siris. 18This syndrome of akinesia has been reported to exist across diagnostic categories such as parkinsonism, retarded depression, and the negative symptoms of schizophrenia. 18 In these diagnoses, reduced dopa-
mine turnover in the brain has been hypothesized to play a part in the pathophysiology of each, although controversies exist. All of the patients had anergia, which suggests that the above-mentioned hypothesis is interesting and requires further investigation. The treatment of negative symptoms in chronically ill schizophrenic patients by selegiline augmentation to enhance dopamine function is an intriguing possibility, as suggested by our case series and the study by Bodkin et al. 2 This strategy needs further evaluation using controlled studies.
REFERENCES 1. Gupta S, Andreasen NC, Amdt S, Flaum MA, Hubbard WC, Ziebell S. The Iowa Prospective Longitudinal Study of Recent Onset Psychoses: one year follow-up of first episode subjects. Schizophr Res. 1997;23:1 - 1 3 . 2. Bodkin AJ, Cohen BM, Salomon MS, Cannon SE, Zornberg GL, Cole JO. Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. J Nerv Ment Dis 1996;184:295301. 3. Tyrer R Towards rational therapy with monoamine oxidase inhibitors. Br J Psychiatry 1976;128:354-360. 4. Cole JO, Jones RT, Klerman GL. Drug therapy. Prog Neurol Psychiatry 1961;16:539-574. 5. Kamman GR, Freeman JG, Lucero R. The effect of iproniazid on the behavior of long-term mental patients. J Nerv Ment Dis 1953;118:391-407. 6. Bucci L. The negative symptoms of schizophrenia and the monoamine oxidase inhibitors. Psychopharmacology 1987;91: 104-108. 7. Siris SG, Van Kammen DE Docherty JR The use of antidepressant medication in schizophrenia: a review of the literature. Arch Gen Psychiatry 1978;35:1367-1377. 8. Yu PH, Bouton AA. Clinical pharmacology of MAO-B inhibitors. In: Kennedy SH (ed): Clinical Advances in Monoamine Oxidase Inhibitor Therapies. Washington, DC: American Psychiatric Association, 1994:61-82. 9. Mackay AVR Positive and negative symptoms and the role of dopamine. Br J Psychiatry 1980;137:379-383.
10. Van Kammen DE Van Kammen WB, Mann LS. Dopamine metabolism in the cerebrospinal fluid of drug-free schizophrenic patients with and without cerebral atrophy. Arch Gen Psychiatry 1986;43:978-983. 11. Weinberger D. The implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660-669. 12. Stein L, Wise CD. Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-hydroxydopamine. Science 1971;171:1032-1036. 13. Rosen J, Silk KR, Rice HE, Smith CB. Platelet alpha 2 adrenergic dysfunction in negative symptom schizophrenia: a preliminary study. Biol Psychiatry 1985;20:539-545. 14. Murray RM, Lewis SM, Reveley AM. Towards an etiological classification of schizophrenia. Lancet 1985;1:10231026. 15. Tandon R, Greden JF. Cholinergic hyperactivity and negative schizophrenic symptoms. Arch Gen Psychiatry 1989;46: 745-753. 16. Bowers MB. Central dopamine turnover in schizophrenic syndromes. Arch Gen Psychiatry 1974;31:50-54. 17. Post RM, Fink E, Carpenter WT, Goodwin FF. Cerebrospinal fluid amine metabolites in acute schizophrenia. Arch Gen Psychiatry 1975;32:1063-1069. 18. Bermanzohn PC, Siris SG. Akinesia: a syndrome common to parkinsonism, retarded depression, and negative symptoms of schizophrenia. Compr Psychiatry 1992;33:221-232.