Beruflich Dokumente
Kultur Dokumente
DRUG THERAPY
ALASTAIR J. J. WOOD, M.D., Editor
Jan. 4, 1996
TO
TREAT SCHIZOPHRENIA
Antipsychotic Drugs
SCHIZOPHRENIA
JOHN MICHAEL KANE, M.D.
Vol. 334
No. 1
DRUG THERAPY
Table 1. Typical Doses and Estimated Relative Potency of Antipsychotic Drugs Available in the United States.
DRUG
EQUIVALENT
DOSE*
jority of patients, and that at this dose the drug has relatively few extrapyramidal side effects (at higher doses,
their incidence increases).
MAINTENANCE
THERAPY
THERAPY
mg
Phenothiazines
Chlorpromazine
Thioridazine
Mesoridazine
Acetophenazine
Prochlorperazine
Perphenazine
Triuoperazine
Triupromazine
Fluphenazine
Thioxanthenes
Thiothixene
Chlorprothixene
Butyrophenones
Haloperidol
Dibenzoxazepines
Loxapine
Dihydroindolones
Molindone
Dibenzodiazepines
Clozapine
Benzisoxazoles
Risperidone
Long-acting injectable
preparations
Fluphenazine decanoate
Haloperidol decanoate
35
mg/day
100
100
50
20
15
10
5
25
2
2001000
200800
100400
60150
60200
1264
1060
30150
550
50400
50400
25200
4080
2060
824
430
20100
115
5
100
1060
50600
630
50400
550
115
10
20160
1060
10
40225
15100
50
300900
200400
48
Unknown
6100 every 24 wk
50200 every 4 wk
*Numbers shown are the numbers of milligrams of the drug required for the dose to be
equivalent to the doses of the other drugs in the table (e.g., 100 mg of chlorpromazine is equivalent to 2 mg of haloperidol). Relative potency may not be the same at higher dosages as at
lower ones.
been established for all drugs.) If compliance is established and the drug is ineffective, a different class of antipsychotic drug should be tried. A second failure would
be an indication for the use of clozapine.
The two new antipsychotic drugs that have been approved in the United States in recent years deserve specic comment. One of them, risperidone, should be included among the rst-line antipsychotic drugs, whereas
the other, clozapine, is indicated only for patients who
do not respond to or cannot tolerate the rst-line drugs.
Risperidone
Risperidone is a benzisoxazole derivative with combined dopamine D2receptor and serotonin 5-HT2
receptorblocking properties; its efcacy was established in seven clinical studies of acutely psychotic
patients.16-22 The extent to which it may be superior to
existing agents for routine treatment or similar to clozapine for refractory patients has not been established. In
a multicenter trial conducted in the United States and
Canada,20,22 6 or 16 mg of risperidone per day was superior to 20 mg of haloperidol per day on some measures of clinical improvement, but other doses (2 and 10
mg per day) were not. It is difcult to draw rm conclusions about the relative efcacy of these agents,
since only one dose of haloperidol but four doses of risperidone were used per day. The available data suggest
that 6 mg of risperidone per day is effective in the ma-
Clozapine
Clozapine has atypical neuropharmacologic characteristics.23 It has relatively high afnity for dopamine
D1 and D4, 5-HT2 , muscarinic, and alpha-adrenergic
receptors, but it is also a dopamine D2receptor antagonist.3,4 It remains the only antipsychotic drug proved
to have superior efcacy in patients in whom multiple
trials of other antipsychotic drugs have failed.11 Whether it is indicated after the failure of only one or two
drugs is not known. Since clozapine causes agranulocytosis current estimates suggest a frequency of 0.8
percent during one year of treatment24 it was approved in 1990 specically for the treatment of patients
who did not respond adequately to standard antipsychotic drug therapy, either because the therapy was not
effective or because it could not be given in adequate
doses as a result of intolerable side effects. Clozapine is
at present the best treatment for patients with refractory psychosis.25 (Other alternatives that are sometimes
helpful for such patients include risperidone, lithium,
benzodiazepines, and electroconvulsive therapy.) In addition to its antipsychotic actions, clozapine may also
help reduce aggressive and hostile behavior 26 and the
risk of suicide.27
Though both clozapine and risperidone have some
advantages over other drugs in terms of reducing socalled negative symptoms (attened affect, avolition,
and impoverished speech or behavior), their benet has
been demonstrated only in relatively short-term trials.11,20,22 Because it is difcult in such studies to distinguish between negative symptoms and drug-induced
parkinsonism, long-term trials focusing on persistent
negative symptoms are needed.
Dosage
36
initiated and considerable improvement may occur within three to ve days, their full effects may not be evident for many weeks or even months. As a rule, half of
the ultimate improvement in psychotic symptoms and
signs (e.g., delusions or hallucinations) occurs in the
rst three to four weeks.40
As measured by PET, 70 to 90 percent of dopamine
receptors are blocked by doses of 300 to 400 mg of
chlorpromazine or thioridazine or 4 to 12 mg of haloperidol.41 In some studies, patients who did not respond
adequately to standard doses still had 80 to 85 percent
blockade of dopamine receptors,42 but in other studies
the antipsychotic effect and the degree of dopamine
D2receptor occupancy were positively correlated.43
Clozapine has good therapeutic efcacy with relatively low dopamine D2receptor occupancy in the basal ganglia (38 to 63 percent).41 Its afnity for dopamine D1 and D4 receptors or other neurotransmitter
systems probably accounts for some of its efcacy.41
The resolution of PET studies, however, is such that receptor occupancy is measured mostly in brain areas
more closely related to adverse effects (extrapyramidal
symptoms) than to therapeutic response.
Equivalent doses of antipsychotic drugs, with chlorpromazine used as the standard, are shown in Table 1.
These estimates are based on group comparisons and
are not necessarily the result of careful studies designed
to establish minimal effective doses or dosage ranges.
For most of these drugs, all or most of the dose can be
given at bedtime, if necessary, in order to minimize adverse effects during the day.
Adverse Effects
Although antipsychotic drugs have an array of adverse effects, their therapeutic index is high. Adverse
effects are rarely serious or irreversible. The most troublesome are neurologic and include acute dystonia,
akathisia (restlessness), parkinsonism, and tardive dyskinesia or tardive dystonia (Table 2).44 Akathisia may
be misdiagnosed as anxiety or psychotic agitation, and
akinesia as depression or as the apathy and restricted
affect that can be associated with schizophrenia. Among
patients receiving short-term treatment, 50 to 70 percent will have some clinically important extrapyramidal side effects. These effects may diminish after two or
three months, but they often persist in some form as
long as the antipsychotic drug is taken.45
The neuroleptic malignant syndrome is a relatively
rare, potentially fatal complication of antipsychotic drug
therapy.46 It usually occurs within the rst few weeks of
treatment or after an increase in the dose and is characterized by high fever, severe muscle rigidity, autonomic
instability, altered consciousness, and elevated serum
creatine kinase concentrations. Treatment consists of
the immediate discontinuation of the antipsychotic drug;
the administration of dantrolene, bromocriptine, or pergolide; and supportive therapy. The mortality in untreated cases can be as high as 20 percent.
Antipsychotic drugs also have a variety of adverse
Jan. 4, 1996
Vol. 334
No. 1
DRUG THERAPY
the neuroleptic malignant syndrome; however, the relative risk in relation to that with other drugs has not
been established.
Overall, depot therapy with antipsychotic drugs has
the same adverse effects as oral administration of the
same drugs and a similar incidence of adverse neurologic effects.52 Antipsychotic drugs are not known to
have teratogenic effects, but they should be used cautiously in pregnant women. Many antipsychotic drugs
are present in small quantities in breast milk, and nursing should therefore be avoided.
Other Drugs Used in the Treatment of Schizophrenia
Lithium
Lithium can have some therapeutic benet in patients with schizophrenia53 and can help as adjunctive
treatment in patients who respond poorly to antipsychotic drugs.54-56 However, the benecial effects of lithium are limited at best, and it is clearly inferior to antipsychotic drugs. Predictors of the response to lithium
in this context have not been established.
Benzodiazepines
37
Although anticonvulsant drugs such as carbamazepine and valproate are effective in patients with manic
depressive illness,68,69 their value in schizophrenia is less
clear. Among these drugs, only carbamazepine has been
studied as an adjunct to antipsychotic drugs. In controlled studies, carbamazepine had some benet as adjunctive therapy, but the effects were small at best.27,70,71
Carbamazepine alone is not an effective maintenance
treatment.72
Antidepressant Drugs
Antidepressant drugs have no role as the sole treatment for schizophrenia but are indicated as an adjunctive treatment in patients with schizophrenia and depression and possibly those with obsessivecompulsive
symptoms or panic attacks. Depression may occur in
patients with schizophrenia after recovery from an
acute psychotic episode73 or at other times. Moreover,
schizophrenia is associated with a high rate of suicide
(lifetime risk, approximately 10 percent). The extent
to which prophylactic treatment with antidepressant
drugs could reduce this risk in selected patients is not
known.
Adjunctive treatment with a tricyclic antidepressant
drug is effective in alleviating symptoms of depression.74 For patients with substantial depressive symptoms, a trial of antidepressant therapy is therefore
justied, as long as clear goals are identied (e.g., amelioration of particular symptoms) and the patient is reassessed regularly. The antidepressant drug should be
given to such patients in the same dosage as to patients
with a major depressive disorder, but combined therapy
with an antipsychotic and an antidepressant drug can
result in higher plasma concentrations of both drugs
than when either is given alone. The risk of exacerbating core psychotic symptoms with an antidepressant
drug is minimal when an antipsychotic drug is also being given and when there is no acute psychotic exacerbation.75 The most appropriate duration of antidepressant therapy, if it is effective, is not known. In a study
of the discontinuation of therapy in patients who had
been treated with imipramine for 6 months, the rate of
relapse was higher among those who were switched
from imipramine to placebo than among those who
continued to receive imipramine during a 12-month follow-up period.76
Antiparkinsonian Drugs
Because antipsychotic drugs often cause adverse extrapyramidal or parkinsonian effects, such as acute
dystonia, akinesia, tremor, rigidity, and akathisia, it is
common practice to administer antiparkinsonian drugs
38
Kane et al.85,86
Fluphenazine (1.25 5 mg)
Fluphenazine (2.5 10 mg)
Fluphenazine (12.5 50 mg)
Jan. 4, 1996
56
24
14
Marder et al.87,88
Fluphenazine (5 10 mg)
Fluphenazine (25 50 mg)
Johnson et al.89
Fluphenazine (mean, 12 mg)
Fluphenazine (mean, 25 mg)
Hogarty et al.90
Fluphenazine (mean, 3.8 mg)
Fluphenazine (mean, 25 mg)
Kane et al.91
Haloperidol (25 mg)
Haloperidol (50 mg)
Haloperidol (100 mg)
Haloperidol (200 mg)
Schooler et al.92
Fluphenazine (2.5 10 mg)
Fluphenazine (12.5 50 mg)
22
20
32
10
22
14
60
25
23
15
29
20
0 10 20 30 40 50 60 70
Vol. 334
No. 1
DRUG THERAPY
33
Carpenter et al.93
55
10
Herz et al.94
29
7
95,96
Jolley et al.
30
15
Pietzcker et al.97
35
20
92
Schooler et al.
32
10
20
30
40
50
60
39
40
17. Borison RL, Pathiraja AP, Diamond BI, Meibach RC. Risperidone: clinical
safety and efcacy in schizophrenia. Psychopharmacol Bull 1992;28:213-8.
18. Claus A, Bollen J, De Cuyper H, et al. Risperidone versus haloperidol in
the treatment of chronic schizophrenic inpatients: a multicentre doubleblind comparative study. Acta Psychiatr Scand 1992;85:295-305.
19. Muller-Spahn F. Risperidone in the treatment of chronic schizophrenic patients: an international double-blind parallel-group study versus haloperidol. Clin Neuropharmacol 1992;15:Suppl 1:90A-91A.
20. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of xed doses of risperidone and haloperidol in the
treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;
13:25-40. [Erratum, J Clin Psychopharmacol 1993;13:149.]
21. Ceskova E, Svestka J. Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses. Pharmacopsychiatry 1993;26:121-4.
22. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia.
Am J Psychiatry 1994;151:825-35.
23. Fitton A, Heel RC. Clozapine: a review of its pharmacological properties,
and therapeutic use in schizophrenia. Drugs 1990;40:722-47.
24. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis: incidence and risk factors in the United
States. N Engl J Med 1993;329:162-7.
25. Christison GW, Kirch DG, Wyatt RJ. When symptoms persist: choosing
among alternative somatic treatments for schizophrenia. Schizophr Bull
1991;17:217-45.
26. Mallya AR, Roos PD, Roebuck-Colgan K. Restraint, seclusion, and clozapine. J Clin Psychiatry 1992;53:395-7.
27. Meltzer HY, Okayli G. Reduction of suicidality during clozapine treatment
in neuroleptic-resistant schizophrenia: impact on risk-benet assessment.
Am J Psychiatry 1995;152:183-90.
28. Quitkin F, Rifkin A, Klein DF. Very high dosage vs standard dosage
uphenazine in schizophrenia: a double-blind study of nonchronic treatment-refractory patients. Arch Gen Psychiatry 1975;32:1276-81.
29. Ericksen SE, Hurt SW, Chang S. Haloperidol dose, plasma levels, and clinical response: a double-blind study. Psychopharmacol Bull 1978;14:15-6.
30. Neborsky R, Janowsky D, Munson E, Depry D. Rapid treatment of acute
psychotic symptoms with high- and low-dose haloperidol: behavior considerations. Arch Gen Psychiatry 1981;38:195-9.
31. McCreadie RG, MacDonald IM. High dosage haloperidol in chronic schizophrenia. Br J Psychiatry 1977;131:310-6.
32. Bjorndal N, Bjerre M, Gerlach J, et al. High dosage haloperidol therapy in
chronic schizophrenic patients: a double-blind study of clinical response,
side effects, serum haloperidol, and serum prolactin. Psychopharmacology
(Berl) 1980;67:17-23.
33. Kinon BJ, Kane JM, Johns C, et al. Treatment of neuroleptic-resistant
schizophrenic relapse. Psychopharmacol Bull 1993;29:309-14.
34. Reardon GT, Rifkin A, Schwartz A, Myerson A, Siris SG. Changing patterns
of neuroleptic dosage over a decade. Am J Psychiatry 1989;146:7269.
35. Remington G, Pollock B, Voineskos G, Reed K, Coulter K. Acutely psychotic patients receiving high-dose haloperidol therapy. J Clin Psychopharmacol 1993;13:41-5.
36. Rifkin A, Doddi S, Karajgi B, Borenstein M, Wachspress M. Dosage of haloperidol for schizophrenia. Arch Gen Psychiatry 1991;48:166-70.
37. Levinson DF, Simpson GM, Singh H, et al. Fluphenazine dose, clinical response, and extrapyramidal symptoms during acute treatment. Arch Gen
Psychiatry 1990;47:761-8.
38. Van Putten T, Marder SR, Mintz J. A controlled dose comparison of haloperidol in newly admitted schizophrenic patients. Arch Gen Psychiatry
1990;47:754-8.
39. Volavka J, Cooper T, Czobor P, et al. Haloperidol blood levels and clinical
effects. Arch Gen Psychiatry 1992;49:354-61.
40. Davis JM, Barter JT, Kane JM. Antipsychotic drugs. In: Kaplan HI, Sadock
BJ, eds. Comprehensive textbook of psychiatry/V. 5th ed. Vol. 2. Baltimore:
Williams & Wilkins, 1989:1591-626.
41. Farde L, Norstrm A-L, Wiesel F-A, Pauli S, Halldin C, Sedvall G. Positron
emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49:538-44.
42. Wolkin A, Barouche F, Wolf AP, et al. Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 1989;146:905-8.
43. Nordstrm A-L, Farde L, Wiesel F-A, et al. Central D2-dopamine receptor
occupancy in relation to antipsychotic drug effects: a double-blind PET
study of schizophrenic patients. Biol Psychiatry 1993;33:227-35.
44. The American Psychiatric Association Task Force on Tardive Dyskinesia.
Tardive dyskinesia: a task force report of the American Psychiatric Association. Washington, D.C.: American Psychiatric Association, 1992.
45. Rifkin A, Quitkin F, Kane J, Struve F, Klein DF. Are prophylactic antiparkinson drugs necessary? A controlled study of procyclidine withdrawal.
Arch Gen Psychiatry 1978;35:483-9.
Jan. 4, 1996
46. Gratz SS, Levinson DF, Simpson GM. Neuroleptic malignant syndrome: In:
Kane JM, Lieberman JA, eds. Adverse effects of psychotropic drugs. New
York: Guilford Press, 1992:266-84.
47. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-B38,
DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with
schizophrenia. Arch Gen Psychiatry 1990;47:945-8.
48. Devinsky O, Pacia SV. Seizures during clozapine therapy. J Clin Psychiatry
1994;55:Suppl B:153-6.
49. Baker RW, Chengappa KN, Baird JW, Steingard S, Christ MA, Schooler
NR. Emergence of obsessive compulsive symptoms during treatment with
clozapine. J Clin Psychiatry 1992;53:439-42.
50. Casey DE. Clozapine: neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology (Berl) 1989;99:Suppl:S47-S53.
51. Kane JM, Woerner MG, Pollack S, Safferman AZ, Lieberman JA. Does
clozapine cause tardive dyskinesia? J Clin Psychiatry 1993;54:327-30.
52. Glazer WM, Kane JM. Depot neuroleptic therapy: an underutilized treatment option. J Clin Psychiatry 1992;53:426-33.
53. Hirschowitz J, Casper R, Garver DL, Chang S. Lithium response in good
prognosis schizophrenia. Am J Psychiatry 1980;137:916-20.
54. Small JG, Kellams JJ, Milstein V, Moore J. A placebo-controlled study of
lithium combined with neuroleptics in chronic schizophrenic patients. Am
J Psychiatry 1975;132:1315-7.
55. Growe GA, Crayton JW, Klass DB, Evans H, Strizich M. Lithium in chronic
schizophrenia. Am J Psychiatry 1979;136:454-5.
56. Carman JS, Bigelow LB, Wyatt RJ. Lithium combined with neuroleptics in
chronic schizophrenic and schizoaffective patients. J Clin Psychiatry 1981;
42:124-8.
57. Wolkowitz OM, Pickar D. Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. Am J Psychiatry 1991;148:714-26.
58. Salzman C, Solomon D, Miyawaki E, et al. Parenteral lorazepam versus
parenteral haloperidol for the control of psychotic disruptive behavior.
J Clin Psychiatry 1991;52:177-80.
59. Garza-Trevino ES, Hollister LE, Overall JE, Alexander WF. Efcacy of
combinations of intramuscular antipsychotics and sedative-hypnotics for
control of psychotic agitation. Am J Psychiatry 1989;146:1598-601.
60. Arana GW, Ornsteen ML, Kanter S, Friedman HL, Greenblatt DJ, Shader
RI. The use of benzodiazepines for psychotic disorders: a literature review
and preliminary clinical ndings. Psychopharmacol Bull 1986;22:77-87.
61. Barbee JG, Mancuso DM, Freed CR, Todorov AA. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry
1992;149:506-10. [Erratum, Am J Psychiatry 1992;149:1129.]
62. Pato CN, Wolkowitz OM, Rapaport M, Schulz SC, Pickar D. Benzodiazepine augmentation of neuroleptic treatment in patients with schizophrenia.
Psychopharmacol Bull 1989;25:263-6.
63. Hanlon TE, Ota KY, Kurland AA. Comparative effects of uphenazine,
uphenazine-chlordiazepoxide and uphenazine-imipramine. Dis Nerv Syst
1970;31:171-7.
64. Wolkowitz OM, Breier A, Doran A, et al. Alprazolam augmentation of the
antipsychotic effects of uphenazine in schizophrenic patients: preliminary
results. Arch Gen Psychiatry 1988;45:664-71.
65. Csernansky JG, Riney SJ, Lombrozo L, Overall JE, Hollister LE. Doubleblind comparison of alprazolam, diazepam, and placebo for the treatment
of negative schizophrenic symptoms. Arch Gen Psychiatry 1988;45:655-9.
66. Menza MA, Harris D. Benzodiazepines and catatonia: an overview. Biol
Psychiatry 1989;26:842-6.
67. Meltzer HY. New drugs for the treatment of schizophrenia. Psychiatr Clin
North Am 1993;16:365-85.
68. Post RM. Non-lithium treatment for bipolar disorder. J Clin Psychiatry
1990;51:Suppl:9-16.
69. Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A doubleblind comparison of valproate and lithium in the treatment of acute mania.
Am J Psychiatry 1992;149:108-11.
70. Simhandl C, Meszaros K. The use of carbamazepine in the treatment of
schizophrenia and schizoaffective psychosis: a review. J Psychiatry Neurosci 1992;17:1-14.
71. Schulz SC, Kahn EM, Baker RW, Conley RR. Lithium and carbamazepine
augmentation in treatment-refractory schizophrenia. In: Angrist B, Schulz
SC, eds. The neuroleptic-nonresponsive patient: characterization and treatment. Washington, D.C.: American Psychiatric Press, 1990:109-36.
72. Carpenter WT Jr, Kurz R, Kirkpatrick B, et al. Carbamazepine maintenance
treatment in outpatient schizophrenics. Arch Gen Psychiatry 1991;48:69-72.
73. Siris SG, van Kammen DP, Docherty JP. The use of antidepressant drugs in
schizophrenia: a review of the literature. Arch Gen Psychiatry 1978;35:
1368-77.
74. Siris SG, Morgan V, Fagerstrom R, Rifkin A, Cooper TB. Adjunctive imipramine in the treatment of postpsychotic depression: a controlled trial. Arch
Gen Psychiatry 1987;44:533-9.
75. Prusoff BA, Williams DH, Weissman MM, Astrachan BM. Treatment of
secondary depression in schizophrenia: a double-blind, placebo-controlled
trial of amitriptyline added to perphenazine. Arch Gen Psychiatry 1979;36:
569-75.
Vol. 334
No. 1
DRUG THERAPY
76. Siris SG, Cutler J, Owen K, Mason S, Gingerich S, Lang MP. Adjunctive
imipramine maintenance treatment in schizophrenic patients with remitted
postpsychotic depression. Am J Psychiatry 1989;146:1495-7.
77. Chien CP, Dimascio A, Cole JO. Antiparkinsonian agents and depot phenothiazine. Am J Psychiatry 1974;131:86-90.
78. Hanlon TE, Schoenrich C, Freinek W, Turek I, Kurland AA. Perphenazinebenztropine mesylate treatment of newly admitted psychiatric patients. Psychopharmacologia 1966;9:328-39.
79. Keepers GA, Clappison VJ, Casey DE. Initial anticholinergic prophylaxis
for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry
1983;40:1113-7.
80. Davis JM. Overview: maintenance therapy in psychiatry. I. Schizophrenia.
Am J Psychiatry 1975;132:1237-45.
81. Kane JM, Lieberman JA. Maintenance pharmacotherapy in schizophrenia.
In: Meltzer HY, ed. Psychopharmacology: the third generation of progress.
New York: Raven Press, 1987:1103-9.
82. Kane JM. Treatment of schizophrenia. Schizophr Bull 1987;13:13356.
83. Kissling W, ed. Guidelines for neuroleptic relapse prevention in schizophrenia. Berlin, Germany: Springer-Verlag, 1991.
84. Davis JM, Matalon L, Watanabe MD, Blake L. Depot antipsychotic drugs:
place in therapy. Drugs 1994;47:741-73. [Erratum, Drugs 1994;48:616.]
85. Kane JM, Rikn A, Woerner MG, et al. Low-dose neuroleptic treatment of
outpatient schizophrenics. I. Preliminary results for relapse rates. Arch Gen
Psychiatry 1983;40:893-6.
86. Kane JM, Woerner MG, Sarantakos S. Depot neuroleptics: a comparative
review of standard, intermediate, and low-dose regimens. J Clin Psychiatry
1986;47:Suppl:30-3.
87. Marder SR, Van Putten T, Mintz J, et al. Costs and benets of two doses of
uphenazine. Arch Gen Psychiatry 1984;41:1025-9.
41
88. Marder SR, Van Putten T, Mintz J, Lebell M, McKenzie J, May PR. Lowand conventional-dose maintenance therapy with uphenazine decanoate:
two-year outcome. Arch Gen Psychiatry 1987;44:518-21.
89. Johnson DA, Ludlow JM, Street K, Taylor RD. Double-blind comparison of
half-dose and standard-dose upenthixol decanoate in the maintenance
treatment of stabilised out-patients with schizophrenia. Br J Psychiatry
1987;151:634-8.
90. Hogarty GE, McEvoy JP, Munetz M, et al. Dose of uphenazine, familial
expressed emotion, and outcome in schizophrenia: results in a two-year
controlled study. Arch Gen Psychiatry 1988;45:797-805.
91. Kane JM, Davis JM, Schooler NR, Marder SR, Brauzer B, Casey DE.
A one-year comparison of four dosages of haloperidol decanoate.
Schizophr Res 1993;9:239-40. abstract.
92. Schooler NR, Keith SJ, Severe JB, Mathews SM. Treatment strategies in
schizophrenia: effects of dosage reduction and family management outcome. Schizophr Res 1993;9:260. abstract.
93. Carpenter WT Jr, Hanlon TE, Heinrichs DW, et al. Continuous versus targeted medication in schizophrenic outpatients: outcome results. Am J Psychiatry 1990;147:1138-48. [Erratum, Am J Psychiatry 1991;148:819.]
94. Herz MI, Glazer WM, Mostert MA, et al. Intermittent vs maintenance medication in schizophrenia: two-year results. Arch Gen Psychiatry 1991;48:333-9.
95. Jolley AG, Hirsch SR, McRink A, Manchanda R. Trial of brief intermittent
neuroleptic prophylaxis for selected schizophrenic outpatients: clinical outcome at one year. BMJ 1989;298:985-90.
96. Jolley AG, Hirsch SR, Morrison E, McRink A, Wilson L. Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients:
clinical and social outcome at two years. BMJ 1990;301:837-42.
97. Pietzcker A, Gaebel W, Kpcke W, et al. Intermittent versus maintenance
neuroleptic long-term treatment in schizophrenia 2-year results of a German multicenter study. J Psychiatr Res 1993;27:321-39.