A Review of Clozapine: An Antipsychotic Treatment-Resistant Schizophrenia
for
Peggy Stephens This report reviews over 25 years of literature of the development, pharmacology, proposed mechanism of action, efficacy, adverse effects, and recommendations for use of clozapine. Clozapine, synthesized in 1960, is an efficacious antipsychotic that rarely causes extrapyramidal side effects. However, in the mid-1970s, it was associated with an increased incidence of agranulocytosis resulting in restrictions of use. Recent trials with treatment-resistant schizophrenic patients found clozapine to be superior to chlorpromazine and haloperidol, fortifying the potential contribution of this drug. This has generated optimism that clozapine will obtain Food and Drug Administration approval. Generally well tolerated, the 1% to 2% risk of agranulocytosis can be minimized with careful patient selection, white blood cell (WBC) count monitoring, and weighing of risks versus benefits for use beyond the relatively safe initial 4-week period. 0 1990 by W. 6. Saunders Company.
C
LOZAPlNE is an efficacious antipsychotic with the unique property of rarely causing extrapyramidal symptoms. ‘-I5 While seen by some as a breakthrough in the development of treatment for schizophrenia, clozapine has elicited much controversy since being associated with an increased incidence of agranulocytosis in 1975. Though currently marketed in 22 countries,‘* in the United States it was available only on an investigational or compassionate need basis until earning Food and Drug Administration approval this year. This report reviews the development, pharmacology and proposed mechanism of action, efficacy, adverse effects and recommendations for use of clozapine. In light of the high prevalence and significant morbidity of schizophrenia, the search has been intense for both an efficacious and well-tolerated antipsychotic. Since the introduction of chlorpromazine in 1952, the efficacy of antipsychotics in attenuating acute psychotic episodes and delaying relapse is well established.‘33’6V’9 Yet these drugs are not unequivocally “antischizophrenic” in that there is incomplete or lack of improvement in some schizophrenic patients and with many aspects of the schizophrenic syndrome, e.g., negative symptoms such as withdrawal, flat affect, and avolition.17 The term neuroleptic, indicating that neurological activity was diminished, seems to have been coined by Delay et al,*’ who performed the first open clinical trials with chlorpromazine. Early investigators assumed the motor slowing that resembled Parkinson’s disease was a conditio sine qua non (i.e., an essential condition) of the fundamental therapeutic action of neuroleptic drugs.2’ When that assumption was refuted, attention shifted to the still ongoing struggle to control the extrapyramidal side effects that, while rarely life-threatening, can make patients extraordinarily uncomfortable, socially stigmatized, and functionally From the Harvard Department of Psychiatry, McLean Hospital. Belmont, MA. Presented at the 1988 Annual Meeting of the Kentucky Psychiatric Association. Address reprint requests to Peggy Stephens, M.D.. M.A.. Harvard Department McLean Hospital, Belmont, MA 02178. G I990 by W.B. Saunders Company. 0010-440x/90/31 04-001 I %03.00/O
Comprehensive
Psychiarry, Vol. 3 1, No. 4 (July/August),
1990: pp 3 16-926
of Psychiatry,
315
316
PEGGY STEPHENS
disabled.‘6*22-25Despite tremendous clinical research efforts, treatment for these common side effects is not always satisfactory or innocuous.16,18,21,23-30 BRIEF HISTORY
The synthesis of clozapine [8-chloro-l l-(4-methyl-L-piperazinyl)-5H-dibenzo (b,e) (1,4) diazepine], a tricyclic dibenzodiazepine derivative related chemically to loxapine, challenged traditional thinking about antipsychotics in 1960. Open clinical trials of clozapine began in 1962. Marketing under the trade name of Leponex (Sandoz, East Hanover, NJ) was initiated in 1972. Early studies concluded “the drug proved to be antipsychotic and practically free of extrapyramida1 side effects but gave rise to neurovegetative side effects, such as hypotension, tachycardia, and salivation . . . in spite of this, however, acceptance was excellent.“’ Still unexplained, in 1975 a high incidence of agranulocytosis was reported in association with clozapine (Leponex) in southwest Finland, resulting in restriction of use. PHARMACOLOGY
Clozapine may be administered orally or intramuscularly. Absorption of oral clozapine is rapid and almost complete, providing a rapid onset of action.31 Duration of action is greater than 24 hours, allowing single bedtime dosing initially if preferred.2*8T’4It is extensively metabolized, and its much weaker metabolites are eliminated in the urine and feces principally in unconjugated form.31 The mean half-life is 15.8 hours (range, 6 to 30 hours) and steady-state is reached within 7 to 10 days of treatment.31’32 At steady-state, there is a linear relationship between administered dose and clozapine plasma concentration.32 In animals, clozapine is clearly distinguished from the classical neuroleptic agents by its failure to induce typical effects of DA receptor blockade: catalepsy, antagonism of apomorphine- or amphetamine-induced stereotyped behaviors, elevated serum prolactin, and dopamine (DA) receptor hypersensitivity following repeated administrations.33 Some of the work that has attempted to elucidate this distinction will be mentioned. Via stimulation of DA receptors in the corpus striatum and/or nucleus accumbens, apomorphine, a direct-acting DA agonist, induces a stereotyped motor behavior in rodents of sniffing, licking, and gnawing. The pharmaceutical industry has used the ability to block apomorphine- or amphetamine-induced stereotyped motor behavior in rodents as a screening test for antipsychotic potency. Subsequently, this test has been correlated with blockade of striatal D-2 receptors labeled In contrast, clozapine is a relatively weak striatal with 3H-butyrophenone.10,‘3~19~34 D-2 receptor antagonist.34W36The recently published work of Farde et a136 with positron emission tomography scan measurement of striatal D-2 receptor blockade reported only 65% receptor blockade after administration of clozapine, as compared with 80% and 84% blockade after chlorpromazine and haloperidol, respectively. Demonstrating that clozapine caused a much higher rate of turnover of DA in the limbic cortex than the striatum, Anden and Stock37 hypothesized the differential affinity of clozapine to the different central dopaminergic systems. The functional DA deficiency in the limbic system was correlated with antipsychotic activity, while extrapyramidal effects paralleled the functional DA deficiency in the striatum.13*37*38
A REVIEW OF CLOZAPINE
317
A number of researchers39-42 have compared the electrophysiological activity of the nigrostriatal (NS) and cortico-limbic (CL) dopaminergic systems after acute and chronic administration of antipsychotics. Neuronal activity was measured in the substantia nigra (A-9) and ventral tegmentum (A-IO), the origins of the NS and CL systems, respectively. Through a mechanism of reduced inhibitory feedback following blockade of striatal DA receptors and autoreceptors on DA neuronal cell bodies in areas A-9 (NS) and A-10 (CL), acute administration of chlorpromazine and haloperidol increased dopaminergic activity in both areas. Clozapine and thioridazine increased dopaminergic activity only in the A-10 (CL) area; whereas metoclopramide, an agent that causes extrapyramidal symptoms but is devoid of antipsychotic activity except at higher doses, increased dopaminergic activity only in area A-9 (NS).39 In contrast, chronic neuroleptic administration has been theorized to produce a depolarization block of the DA neurons.41*42 Chronic treatment with chlorpromazine and haloperidol resulted in a marked reduction in both area A-9 (NS) and A-10 (CL) dopaminergic activity. Chronic clozapine and thioridazine treatment resulted in decreased activity in only area A-10 (CL), with metoclopramide reducing dopaminergic activity only in area A-9 (NS). Creese,13 described a mechanism of dynamic changes in the dopamine system to explain the temporal characteristics of the clinical response to antipsychotics. After a few weeks, depolarization block of dopamine neurons occurs as homeostatic mechanisms fail to maintain dopaminergic activity despite neuroleptic-induced D-2 receptor blockage. The antipsychotic effect of the drug, along with extrapyramidal side effects, is enhanced at this time. Atypical neuroleptics, such as clozapine and thioridazine, are effective antipsychotics by blocking activity in the A-10 (CL) area. However, they do not produce the depolarization block in the A-9 (NS) area, thus causing fewer extrapyramidal side effects.13 Most studies report that dopamine receptor hypersensitivity does not appear to occur with clozapine. 13*31.33*44-46 However, Ekblom et a1.47described two cases of pronounced deterioration of psychosis within 24 to 48 hours after sudden clozapine withdrawal. The authors postulated the deterioration was due to a clozapineinduced supersensitivity of the mesolimbic DA receptors. Similarly, Simpson et al.48 reported the return of severe psychosis within 3 to 6 days following clozapine discontinuation in three patients. Within 2 weeks, the patients were returning to their initial baseline. Work by Gerbino et al., 3owho reduced doses 50% to 60% for maintenance therapy without recurrence of symptoms, suggest patients should be gradually tapered off the medication. Only slight, transient elevations in serum prolactin levels occur, suggesting the tubero-hypophysial dopaminergic system is relatively unaffected by clozapine.31*49.50 Though not correlated with clinical potency as an antipsychotic agent, the role of muscarinic cholinergic receptor affinity has received considerable attention in attempts to explain the unique clinical profile of clozapine. In animal studies comparing DA turnover, Anden and Stock3’ presented data that administration of clozapine with high muscarinic receptor affinity, induced a greater percentage rise of homovanillac acid in the limbic system than in the corpus striatum. Haloperidol induced similar results only in combination with an anticholinergic drug, leading to
318
PEGGY STEPHENS
the hypothesis that anticholinergic activity may protect against extrapyramidal side effects.37.38,5’ Clozapine, almost devoid of extrapyramidal side effects, is the most potent muscarinic antagonist,‘,‘3’3’*34*51 while butyrophenones with a high frequency of extrapyramidal side effects have a very low affinity for muscarinic receptors.34*51 Molindone, the least potent muscarinic antagonist, is an exception to this inverse relationship in that it only causes a moderate frequency of extrapyramidal side effects.34,52q53 Additional evidence also suggests the mechanism is far more complex than simply an agent’s anticholinergic properties counteracting its DA-blocking effects.‘0*31 Clozapine is also a potent antiserotonergic, antihistaminic, and antiadrenergic agent. 1,8.31,34,35,54 ANTIPSYCHOTIC
EFFICACY
Summary of the data has consistently shown clozapine to be an effective antipsychotic. Indeed, clozapine has been shown to be superior to chlorpromazine and haloperidol in the treatment of recalcitrant schizophrenia.2,“,20,54-58Honigfeld et a1.33reviewed the results of four key US double-blind studies comparing the efficacy of clozapine with chlorpromazine and haloperidol. The Brief Psychiatric Rating Scale (BPRS),59 the Clinical Global Impressions Scale (CGI), and the Nurse’s Observation Scale for Inpatient Evaluation (NOSIE)60 were used to assess therapeutic response in nearly 500 schizophrenic subjects. Most of the patients were selected because of poor response to neuroleptics and/or sensitivity to extrapyramida1 side effects. The data indicated that clozapine was uniformly more effective in treatment-resistant patients and exhibited more rapid onset of action than chlorpromazine or haloperidol. Recently, Kane et al. reported results of a multicenter, double-blind comparison trial that involved 268 carefully selected, treatmentrefractory schizophrenic patients.54 The overall superiority of clozapine was demonstrated, with clozapine being associated with a 30% favorable improvement rate compared with 4% improvement with chlorpromazine/benztropine and less than 2% improvement during a 6-week pretrial with haloperidol/benztropine.54 All five studies found clozapine to be more effective in the treatment of the negative symptoms of schizophrenia that typically are less responsive to standard neuroleptics. (See Table 1 for review of five key studies.) Other published studies support the rapid onset and superior efficacy of clozapine in severely ill and/or treatmentresistant schizophrenic patients, as measured by clinical assessments, discharge rates, employability, and compliance.2~3~7~‘0~“~‘4~57 EXTRAPYRAMIDAL
SIDE EFFECTS
Clozapine rarely produces extrapyramidal side effects. No documented cases of The estimated incidence of clozapine-induced dystonia have been reported. 12,54,56*61 tremor (6.8%), hypokinesia (4,5%), akathisia (4.1%), and rigidity (2.7%)61 is much Not uncommonly, the tremor improved lower than with standard drugs. *J’J**~~~~‘~~* over time without reduction in dose. *v5’Interestingly, in a recent open trial study using clozapine to treat tremors, 17 of 23 patients with essential and/or parkinsonian tremor were greatly improved with clozapine at low doses of 18 to 75 mg/d.63 A recently published, large, multicenter, US double-blind study reports that
A REVIEW
319
OF CLOZAPINE
Table 1. Comparative
Efficacy: Clorapine Versus Chlorpromazine Clozapine Versus Haloperidol
CLOZ Y. CPZI Cogentin (US Multicenter; Kane) No. of subjects Proven faster by day 20 BPRS “positive” symptoms Conceptual disorganization Mannerisms/posturing Hostility Suspiciousness Hallucinatory behavior Excitmsnt Unusual thought Grandiosity BPRS “negative” symptoms Emotional withdrawal Uncooperativeness Blunted affect Diswientation Motor retardation BPRS General Symptoms Somatic cc~ncsm Anxiety Guilt Tension Depressed mood BPRS total SCDT~ Clinical global impresston
t
268 +
+++++ +++++ +++++ +++++ +++++ +++++ +++++ =
CL02 v. CPZ land Placebo) IUS: Shopsinl 39
CLOZ Y. CPZ (US Multicenter; Claghornl 151
++
+++++
+ + ++ + ++++ +++ +++ +
++++
+++++ +++++ +++++ ++++t +++
+ ++ + +
++++ = = +++++ = +++++ +++++
+ ++ = + ++ +++ +
4
+ +++ +++ ++ +++ ++++
CL02 v. CPZ (European Multicenter; FischerCot”elsse”1 223 ++t+
+tt ++t t t tt ++t+ t
+++++ ++++ +++++ tt +++
+t+ ttt t +t+ +
+ ++++ +
_ tttt t t+ t +++
+A+++ +++ +++++ tt++
t + t W’
for
Peggy Stephens This report reviews over 25 years of literature of the development, pharmacology, proposed mechanism of action, efficacy, adverse effects, and recommendations for use of clozapine. Clozapine, synthesized in 1960, is an efficacious antipsychotic that rarely causes extrapyramidal side effects. However, in the mid-1970s, it was associated with an increased incidence of agranulocytosis resulting in restrictions of use. Recent trials with treatment-resistant schizophrenic patients found clozapine to be superior to chlorpromazine and haloperidol, fortifying the potential contribution of this drug. This has generated optimism that clozapine will obtain Food and Drug Administration approval. Generally well tolerated, the 1% to 2% risk of agranulocytosis can be minimized with careful patient selection, white blood cell (WBC) count monitoring, and weighing of risks versus benefits for use beyond the relatively safe initial 4-week period. 0 1990 by W. 6. Saunders Company.
C
LOZAPlNE is an efficacious antipsychotic with the unique property of rarely causing extrapyramidal symptoms. ‘-I5 While seen by some as a breakthrough in the development of treatment for schizophrenia, clozapine has elicited much controversy since being associated with an increased incidence of agranulocytosis in 1975. Though currently marketed in 22 countries,‘* in the United States it was available only on an investigational or compassionate need basis until earning Food and Drug Administration approval this year. This report reviews the development, pharmacology and proposed mechanism of action, efficacy, adverse effects and recommendations for use of clozapine. In light of the high prevalence and significant morbidity of schizophrenia, the search has been intense for both an efficacious and well-tolerated antipsychotic. Since the introduction of chlorpromazine in 1952, the efficacy of antipsychotics in attenuating acute psychotic episodes and delaying relapse is well established.‘33’6V’9 Yet these drugs are not unequivocally “antischizophrenic” in that there is incomplete or lack of improvement in some schizophrenic patients and with many aspects of the schizophrenic syndrome, e.g., negative symptoms such as withdrawal, flat affect, and avolition.17 The term neuroleptic, indicating that neurological activity was diminished, seems to have been coined by Delay et al,*’ who performed the first open clinical trials with chlorpromazine. Early investigators assumed the motor slowing that resembled Parkinson’s disease was a conditio sine qua non (i.e., an essential condition) of the fundamental therapeutic action of neuroleptic drugs.2’ When that assumption was refuted, attention shifted to the still ongoing struggle to control the extrapyramidal side effects that, while rarely life-threatening, can make patients extraordinarily uncomfortable, socially stigmatized, and functionally From the Harvard Department of Psychiatry, McLean Hospital. Belmont, MA. Presented at the 1988 Annual Meeting of the Kentucky Psychiatric Association. Address reprint requests to Peggy Stephens, M.D.. M.A.. Harvard Department McLean Hospital, Belmont, MA 02178. G I990 by W.B. Saunders Company. 0010-440x/90/31 04-001 I %03.00/O
Comprehensive
Psychiarry, Vol. 3 1, No. 4 (July/August),
1990: pp 3 16-926
of Psychiatry,
315
316
PEGGY STEPHENS
disabled.‘6*22-25Despite tremendous clinical research efforts, treatment for these common side effects is not always satisfactory or innocuous.16,18,21,23-30 BRIEF HISTORY
The synthesis of clozapine [8-chloro-l l-(4-methyl-L-piperazinyl)-5H-dibenzo (b,e) (1,4) diazepine], a tricyclic dibenzodiazepine derivative related chemically to loxapine, challenged traditional thinking about antipsychotics in 1960. Open clinical trials of clozapine began in 1962. Marketing under the trade name of Leponex (Sandoz, East Hanover, NJ) was initiated in 1972. Early studies concluded “the drug proved to be antipsychotic and practically free of extrapyramida1 side effects but gave rise to neurovegetative side effects, such as hypotension, tachycardia, and salivation . . . in spite of this, however, acceptance was excellent.“’ Still unexplained, in 1975 a high incidence of agranulocytosis was reported in association with clozapine (Leponex) in southwest Finland, resulting in restriction of use. PHARMACOLOGY
Clozapine may be administered orally or intramuscularly. Absorption of oral clozapine is rapid and almost complete, providing a rapid onset of action.31 Duration of action is greater than 24 hours, allowing single bedtime dosing initially if preferred.2*8T’4It is extensively metabolized, and its much weaker metabolites are eliminated in the urine and feces principally in unconjugated form.31 The mean half-life is 15.8 hours (range, 6 to 30 hours) and steady-state is reached within 7 to 10 days of treatment.31’32 At steady-state, there is a linear relationship between administered dose and clozapine plasma concentration.32 In animals, clozapine is clearly distinguished from the classical neuroleptic agents by its failure to induce typical effects of DA receptor blockade: catalepsy, antagonism of apomorphine- or amphetamine-induced stereotyped behaviors, elevated serum prolactin, and dopamine (DA) receptor hypersensitivity following repeated administrations.33 Some of the work that has attempted to elucidate this distinction will be mentioned. Via stimulation of DA receptors in the corpus striatum and/or nucleus accumbens, apomorphine, a direct-acting DA agonist, induces a stereotyped motor behavior in rodents of sniffing, licking, and gnawing. The pharmaceutical industry has used the ability to block apomorphine- or amphetamine-induced stereotyped motor behavior in rodents as a screening test for antipsychotic potency. Subsequently, this test has been correlated with blockade of striatal D-2 receptors labeled In contrast, clozapine is a relatively weak striatal with 3H-butyrophenone.10,‘3~19~34 D-2 receptor antagonist.34W36The recently published work of Farde et a136 with positron emission tomography scan measurement of striatal D-2 receptor blockade reported only 65% receptor blockade after administration of clozapine, as compared with 80% and 84% blockade after chlorpromazine and haloperidol, respectively. Demonstrating that clozapine caused a much higher rate of turnover of DA in the limbic cortex than the striatum, Anden and Stock37 hypothesized the differential affinity of clozapine to the different central dopaminergic systems. The functional DA deficiency in the limbic system was correlated with antipsychotic activity, while extrapyramidal effects paralleled the functional DA deficiency in the striatum.13*37*38
A REVIEW OF CLOZAPINE
317
A number of researchers39-42 have compared the electrophysiological activity of the nigrostriatal (NS) and cortico-limbic (CL) dopaminergic systems after acute and chronic administration of antipsychotics. Neuronal activity was measured in the substantia nigra (A-9) and ventral tegmentum (A-IO), the origins of the NS and CL systems, respectively. Through a mechanism of reduced inhibitory feedback following blockade of striatal DA receptors and autoreceptors on DA neuronal cell bodies in areas A-9 (NS) and A-10 (CL), acute administration of chlorpromazine and haloperidol increased dopaminergic activity in both areas. Clozapine and thioridazine increased dopaminergic activity only in the A-10 (CL) area; whereas metoclopramide, an agent that causes extrapyramidal symptoms but is devoid of antipsychotic activity except at higher doses, increased dopaminergic activity only in area A-9 (NS).39 In contrast, chronic neuroleptic administration has been theorized to produce a depolarization block of the DA neurons.41*42 Chronic treatment with chlorpromazine and haloperidol resulted in a marked reduction in both area A-9 (NS) and A-10 (CL) dopaminergic activity. Chronic clozapine and thioridazine treatment resulted in decreased activity in only area A-10 (CL), with metoclopramide reducing dopaminergic activity only in area A-9 (NS). Creese,13 described a mechanism of dynamic changes in the dopamine system to explain the temporal characteristics of the clinical response to antipsychotics. After a few weeks, depolarization block of dopamine neurons occurs as homeostatic mechanisms fail to maintain dopaminergic activity despite neuroleptic-induced D-2 receptor blockage. The antipsychotic effect of the drug, along with extrapyramidal side effects, is enhanced at this time. Atypical neuroleptics, such as clozapine and thioridazine, are effective antipsychotics by blocking activity in the A-10 (CL) area. However, they do not produce the depolarization block in the A-9 (NS) area, thus causing fewer extrapyramidal side effects.13 Most studies report that dopamine receptor hypersensitivity does not appear to occur with clozapine. 13*31.33*44-46 However, Ekblom et a1.47described two cases of pronounced deterioration of psychosis within 24 to 48 hours after sudden clozapine withdrawal. The authors postulated the deterioration was due to a clozapineinduced supersensitivity of the mesolimbic DA receptors. Similarly, Simpson et al.48 reported the return of severe psychosis within 3 to 6 days following clozapine discontinuation in three patients. Within 2 weeks, the patients were returning to their initial baseline. Work by Gerbino et al., 3owho reduced doses 50% to 60% for maintenance therapy without recurrence of symptoms, suggest patients should be gradually tapered off the medication. Only slight, transient elevations in serum prolactin levels occur, suggesting the tubero-hypophysial dopaminergic system is relatively unaffected by clozapine.31*49.50 Though not correlated with clinical potency as an antipsychotic agent, the role of muscarinic cholinergic receptor affinity has received considerable attention in attempts to explain the unique clinical profile of clozapine. In animal studies comparing DA turnover, Anden and Stock3’ presented data that administration of clozapine with high muscarinic receptor affinity, induced a greater percentage rise of homovanillac acid in the limbic system than in the corpus striatum. Haloperidol induced similar results only in combination with an anticholinergic drug, leading to
318
PEGGY STEPHENS
the hypothesis that anticholinergic activity may protect against extrapyramidal side effects.37.38,5’ Clozapine, almost devoid of extrapyramidal side effects, is the most potent muscarinic antagonist,‘,‘3’3’*34*51 while butyrophenones with a high frequency of extrapyramidal side effects have a very low affinity for muscarinic receptors.34*51 Molindone, the least potent muscarinic antagonist, is an exception to this inverse relationship in that it only causes a moderate frequency of extrapyramidal side effects.34,52q53 Additional evidence also suggests the mechanism is far more complex than simply an agent’s anticholinergic properties counteracting its DA-blocking effects.‘0*31 Clozapine is also a potent antiserotonergic, antihistaminic, and antiadrenergic agent. 1,8.31,34,35,54 ANTIPSYCHOTIC
EFFICACY
Summary of the data has consistently shown clozapine to be an effective antipsychotic. Indeed, clozapine has been shown to be superior to chlorpromazine and haloperidol in the treatment of recalcitrant schizophrenia.2,“,20,54-58Honigfeld et a1.33reviewed the results of four key US double-blind studies comparing the efficacy of clozapine with chlorpromazine and haloperidol. The Brief Psychiatric Rating Scale (BPRS),59 the Clinical Global Impressions Scale (CGI), and the Nurse’s Observation Scale for Inpatient Evaluation (NOSIE)60 were used to assess therapeutic response in nearly 500 schizophrenic subjects. Most of the patients were selected because of poor response to neuroleptics and/or sensitivity to extrapyramida1 side effects. The data indicated that clozapine was uniformly more effective in treatment-resistant patients and exhibited more rapid onset of action than chlorpromazine or haloperidol. Recently, Kane et al. reported results of a multicenter, double-blind comparison trial that involved 268 carefully selected, treatmentrefractory schizophrenic patients.54 The overall superiority of clozapine was demonstrated, with clozapine being associated with a 30% favorable improvement rate compared with 4% improvement with chlorpromazine/benztropine and less than 2% improvement during a 6-week pretrial with haloperidol/benztropine.54 All five studies found clozapine to be more effective in the treatment of the negative symptoms of schizophrenia that typically are less responsive to standard neuroleptics. (See Table 1 for review of five key studies.) Other published studies support the rapid onset and superior efficacy of clozapine in severely ill and/or treatmentresistant schizophrenic patients, as measured by clinical assessments, discharge rates, employability, and compliance.2~3~7~‘0~“~‘4~57 EXTRAPYRAMIDAL
SIDE EFFECTS
Clozapine rarely produces extrapyramidal side effects. No documented cases of The estimated incidence of clozapine-induced dystonia have been reported. 12,54,56*61 tremor (6.8%), hypokinesia (4,5%), akathisia (4.1%), and rigidity (2.7%)61 is much Not uncommonly, the tremor improved lower than with standard drugs. *J’J**~~~~‘~~* over time without reduction in dose. *v5’Interestingly, in a recent open trial study using clozapine to treat tremors, 17 of 23 patients with essential and/or parkinsonian tremor were greatly improved with clozapine at low doses of 18 to 75 mg/d.63 A recently published, large, multicenter, US double-blind study reports that
A REVIEW
319
OF CLOZAPINE
Table 1. Comparative
Efficacy: Clorapine Versus Chlorpromazine Clozapine Versus Haloperidol
CLOZ Y. CPZI Cogentin (US Multicenter; Kane) No. of subjects Proven faster by day 20 BPRS “positive” symptoms Conceptual disorganization Mannerisms/posturing Hostility Suspiciousness Hallucinatory behavior Excitmsnt Unusual thought Grandiosity BPRS “negative” symptoms Emotional withdrawal Uncooperativeness Blunted affect Diswientation Motor retardation BPRS General Symptoms Somatic cc~ncsm Anxiety Guilt Tension Depressed mood BPRS total SCDT~ Clinical global impresston
t
268 +
+++++ +++++ +++++ +++++ +++++ +++++ +++++ =
CL02 v. CPZ land Placebo) IUS: Shopsinl 39
CLOZ Y. CPZ (US Multicenter; Claghornl 151
++
+++++
+ + ++ + ++++ +++ +++ +
++++
+++++ +++++ +++++ ++++t +++
+ ++ + +
++++ = = +++++ = +++++ +++++
+ ++ = + ++ +++ +
4
+ +++ +++ ++ +++ ++++
CL02 v. CPZ (European Multicenter; FischerCot”elsse”1 223 ++t+
+tt ++t t t tt ++t+ t
+++++ ++++ +++++ tt +++
+t+ ttt t +t+ +
+ ++++ +
_ tttt t t+ t +++
+A+++ +++ +++++ tt++
t + t W’
