- Email: [email protected]
Clozapine withdrawal effects and receptor profiles of typical and atypical neuroleptics
COMMENTARY Clozapine Withdrawal Effects and Receptor Profiles of Typical and Atypical Neuroleptics Cherian Verghese, Jose DeLeon, Chand Nair, and George M. Simpson
Withdrawal effects of neuroleptics have not received much attention. Clozapine withdrawal phenomena have been attributed to psychosis arising from D2 supersensitivity, which is unlikely since it has minimal action on D2 receptors. The time course and clinical features of this phenomenon suggest that cholinergic overdrive and gamma-aminobutyric acid (GABA) supersensitivity occurs after withdrawal, since it is strongly anticholinergic and has a GABAergic action. Recently, a number of patients showed marked decompensation when they were switched from clozapine to risperidone, especially when they were rapidly tapered off clozapine. This was probably more due to withdrawal effects than the primary psychosis or a lack of efficacy of risperidone. A slow withdrawal schedule would facilitate homeostatic mechanisms; anticholinergics would be useful in clozapine withdrawal. This area has not received any attention from researchers, nor are there any guidelines for clinicians. This will be particularly important with the widespread use of atypical agents in the future.
Key Words: Clozapine, risperidone, substance withdrawal syndrome, neuroleptics, anticholinergics, dopamine receptors BIOL PSYCRIATRY 1996;39:135--138
Introduction The atypical neuroleptics, clozapine and risperidone have significantly improved the outlook for treating psychoses. However, as the use of these drugs widens, clinicians are facing difficulties while withdrawing patients from one group of drugs and switching them to others. This is particularly so in the case of clozapine, where it has been postulated that withdrawal is associated with a supersensitivity psychosis or rebound psychosis (Ekblom et al, From the MCP/NSH Clinical Research Center, Norristown State Hospital, Norristown, PA (CV, JD, CN) and the Medical College of PA/EPPI, Philadelphia, PA (GMS). Address reprint requests to Cherian Verghese, MD, MCP/NSH Clinical Research Center, Bldg. 52, Norristown State Hospital, Norristown, PA 19401. Received July 13, 1992; revised December 14, 1994.
© 1996 Society of Biological Psychiatry
1984; Borison et al 1988) in accordance with the hypothesis of Chouinard and Jones (1980). Data on the effects of rapid withdrawal of clozapine suggest that symptoms present within 2-3 days, usually in the first 2 weeks. Anxiety, insomnia, motor restlessness or mute withdrawal, psychotic symptoms, tardive dyskinesia, altered consciousness, confusion, nausea, and diaphoresis are reported (Simpson and Varga 1974; Simpson et al 1978; Perenyi et al 1985; Ekblom et al 1984; Alphs and Lee 1991; Eklund 1987; Borison et al 1988). The exact incidence of these symptoms is not known, although the sudden withdrawal of clozapine from the market in 1977 resulted in psychotic exacerbations in many Finnish hospitals, with one report suggesting an incidence of 39% (Kuha 1977). 0006-3223/96/$15.00 SSDI 0006-3223(95)00215-3
136
BIOLPSYCHIATRY 1996;39:135-138
Clozapine interacts with all the conventional neurotransmitters; it has less D2 affinity at clinically relevant doses, and preferentially blocks D1 (Coward et al 1989), which was confirmed with positron emission tomography (PET) studies using 11C-SCH-23390 as a ligand (Farde et al 1989). Action at D3 (Sokoloff 1990) and D4 receptors (Van Tol et al 1991) is also reported, along with 5-HTIC, 5-HT2, alpha 1 and histamine H1 receptors (Coward 1992). Its anticholinergic action is stronger than that of other neuroleptics, and is comparable to that of atropine (Snyder et al 1974). Chronic clozapine treatment increases GABA turnover in the substantia nigra, unlike typical neuroleptics, which produce the opposite effect (Marco et al 1978). We believe that many of the symptoms of acute clozapine withdrawal could be due to cholinergic overdrive, which occurs in response to its strong anticholinergic action. Dilsaver and Greden (1984) reported that the sudden withdrawal of tricyclic antidepressants, which are strongly anticholinergic, mimics the effects of the administration of cholinomimetics, which consist of (1) general somatic symptoms--a flulike syndrome (malaise, muscle aches, hot and cold flashes, sweating, anergy) and gastrointestinal symptoms (nausea, vomiting, pain, diarrhea), (2) mental symptoms--irritability, anxiety, motor overactivity or withdrawal, (3) sleep disturbances--insomnia, drowsiness, rapid eye movement rebound associated with vivid terrifying dreams, and (4) a movement disorder such as Parkinsonism. These symptoms developed within hours to 2-3 days after drug withdrawal; these symptoms were improved by atropine (Dilsaver et al 1983). The time scale for the onset of symptoms coincides with that in the reports of clozapine withdrawal. It is interesting to note that anticholinergic withdrawal does not only result in somatic symptoms. Studies done with psychotic patients under double-blind placebo-controlled conditions showed that anticholinergic withdrawal also resulted in hallucinations and psychotic symptoms in spite of continued antipsychotic coverage (Simpson et al 1965, Jellinek et al 1981). Thus the symptoms and time course of clozapine and anticholinergic withdrawal seem to be closely correlated. Supersensitivity psychosis (Chouinard 1990) is said to occur within 3 months of stopping typical neuroleptics, which is a different time scale from what is observed here. It is said to occur due to a presumed postsynaptic D2 supersensitivity after chronic D2 blockade. However, chronic clozapine treatment is not associated with increased D2 binding (O'Dell et al 1990) or D2 receptor supersensitivity (Coward 1992). Borison and colleagues (1988) argued for the presence of a supersensitivity psychosis on clozapine withdrawal. In this report, patients who underwent acute clozapine withdrawal had more
C. Verghese et al
symptoms than those who were acutely withdrawn from a chlorpromazine-benztropine combination. The authors argued that the latter combination would have as much anticholinergic action as clozapine, and since the clozapine group had more symptoms, this suggests that cholinergic mechanisms did not play a role here. However, chlorpromazine has numerous active metabolites and a very long half-life, which could have ensured a gradual tapering of anticholinergic effects. Conversely, in the clozapine group, due to the relatively short half-life of the drug, there would have been a sudden anticholinergic withdrawal, which could account for the differences in the symptoms experienced by the two groups. Various other factors may contribute to the withdrawal phenomenon, including the withdrawal effects of other neurotransmitter systems that clozapine acts on, GABA for instance. The worsening of tardive dyskinesia on clozapine withdrawal is felt to be indirect proof of dopamine supersensitivity. Chronic use of typical neuroleptics is associated with GABAergic supersensitivity in the substantia nigra (Frey et al 1987), along with a decrease in glutamic acid decarboxylase activity and GABA turnover. It is felt that these factors may be implicated in tardive dyskinesia (Gale 1980), and GABA agonists have been found to be useful in the treatment of tardive dyskinesia (Thaker et al 1990). Clozapine treatment is associated with increased GABA turnover in the substantia nigra (Marco et al 1978), and clozapine withdrawal is associated with significant GABA supersensitivity, which develops after 1 week, and returns to normal by 2 weeks (Coward et al 1989). This may account for the amelioration of tardive dyskinesia with clozapine treatment, and the worsening seen in the few weeks after withdrawal. Clinically, these data suggest that whenever possible, clozapine should be slowly tapered down, probably at the same rate at which it was tapered up. If side effects necessitate rapid withdrawal, the use of anticholinergics would help to ameliorate at least some of the symptoms. On a larger plane, the issue of withdrawing from and switching between neuroleptics is topical because the newer generation of atypical neuroleptics has a receptor profile that differs from that of typical neuroleptics and clozapine. Many of these agents have combined dopamine and serotonin blocking action, with minimal anticholinergic activity (Gerlach 1991). Clinical reports of clozapine withdrawal phenomena were reported more frequently after its reintroduction in the late 1980s. Recently, with the introduction of risperidone, a number of patients were switched from clozapine to risperidone, often with a rapid taper schedule. Many clinicians reported dramatic decompensation in some patients, often with the above-mentioned features; unfortunately some patients did not restitute as well as would be expected.
Withdrawal from Typical and Atypical Neuroleptics
The issue was not as relevant with the typical neuroleptics, many of which have overlapping profiles of action and, at the very least, they all shared D2 receptor blocking action, which was equipotent at clinically comparable doses. Consequently, it was not very important to consider the exact receptor profile of the previous neuroleptic and the one being introduced. However, this may not be so with the widespread use of atypical agents. Clozapine seems to be in a class of its own with minimal D2 action and strong affinity for all the other major neurotransmitters. Risperidone has a weaker affinity for D2 receptors than haloperidol, and blocks 5-HT2A receptors (Leysen et al 1994). Many of the antipsychotics being developed have a similar combined action on serotonin and dopamine systems. Clinicians need to be aware of the withdrawal effects of a drug when it is discontinued, and whether the new agent being introduced shares a similar receptor profile which would cover withdrawal effects. A similar situation emerged in the field of anxiolytic therapy with the introduction of buspirone (5-HT1A agonist) for the treatment of anxiety. Buspirone has no affinity for G A B A
BIOLPSYCHIATRY 1996;39:135-138
137
receptors and has no cross tolerance with the benzodiazepines; a number of patients developed serious benzodiazepine withdrawal when they were switched to buspirone. This was borne out in a placebo controlled trial (Ashton et al 1990). In these situations, a slow taper schedule, maybe over several weeks, could enable homeostatic mechanisms to restabilize. Again, a slow change over from typical to atypical agents with overlapping dosing schedules may help to avoid withdrawal reactions and psychotic flareups. We are not aware of any systematic studies or even logically evolved guidelines on the subject. Attention to these issues would help patients and clinicians and may ensure that these newer agents do not get a "bad press" in the earlier stages of their introduction.
Dr. Verghese is partially supported by a NARSAD Young Investigator Award. Dr. Simpson is partially supported by a PAL NIMH grant (MH 45190).
References Alphs LD, Lee HS (1991): Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study. J Clin Psychiatry 52:346-348. Ashton CH, Rawlins MD, Tyrer SP (1990): A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry 157:232-238. Borison RL, Diamond BI, Sinha D, Gupta RP, Prince Ajiboye A (1988): Clozapine withdrawal rebound psychosis. Psychopharmacol Bull 24:260-263. Chouinard G (1990): Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 5:21-33. Chouinard G, Jones BD (1980): Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 137:16-21. Coward DM (1992): General pharmacology of clozapine. Br J Psychiatry (supplement) 17:5-11. Coward DM, Imperato A, Urwyler S, White TG (1989): Biochemical and behavioral properties of clozapine. Psychopharmacology 99:$6-S12. Dilsaver SC, Feinberg M, Greden JF (1983): Antidepressant withdrawal symptoms treated with anticholinergic agents. Am J Psychiatry 140:249-251. Dilsaver SC, Greden JF (1984): Antidepressant withdrawal phenomena. Biol Psychiatry 19:237-256. Ekblom B, Eriksson K, Lindstrom LH (1984): Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology 83:293-294. Eklund K (1987): Supersensitivity and clozapine withdrawal. Psychopharmacology 91:135.
Farde L, Wiesel F-A, Nordstrom A-L, Sedvall G (1989): D1 and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99:$28-$31. Frey JM, Ticku MK, Hoffman RD (1987): GABAergic supersensitivity within the pars reticulata of the rat substantia nigra following chronic haloperidol administration. Brain Res 425: 73- 84. Gale K (1980): Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature 283:569-570. Gerlach J (1991): New antipsychotics: Classification, efficacy, and adverse effects. Schizophr Bull 17:289-309. Jellinek T, Gardos G, Cole J (1981): Adverse effects of antiparkinson drug withdrawal. Am J Psychiatry 138:1567-1571. Kuha S (1977): The consequences of sudden stopping of clozapine in Finland. In Vlth World Congress of Psychiatry, Honolulu, Am Psychiatr Assoc Abstracts 813:153. Leysen JE, Janssen PM, Megens AA, Schotte A (1994): Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry 55(suppl):5-12. Marco E, Mao CC, Revuelata A, Peralta E, Costa E (1978): Turnover rates of gamma-aminobutyric acid in substantia nigra, N. caudatus, globus pallidus and N. accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics. Neuropharmacology 17:589-596. O'Dell SJ, La Hoste GJ, Widmark CB, Shapiro RM, Potldn SG, Marshall JF (1990): Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse 6:146-153. Perenyi A, Kuncz E, Bagdy G (1985): Early relapse after sudden
138
BIOL PSYCHIATRY 1996;39:135-138
withdrawal or dose reduction of clozapine. Psychopharmacology 86:244. Simpson GM, Amin M, Kunz E (1965): Withdrawal effects of phenothiazines. Compr Psychiatry 6:347-351. Simpson GM, Lee JH, Shrivastava RK (1978): Clozapine in tardive dyskinesia. Psychopharmacology 56:75-80. Simpson GM, Varga E (1974): CIozapine--A new antipsychotic agent. Curt Ther Res 16:679-686. Snyder S, Greenberg D, Yamamura HI (1974): Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 31:58-61. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC
C. Verghese et al
(1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146-151. Thaker GK, Nguyen JA, Strauss ME, Jocobson T, Kaup BA, Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146-151. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991): Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610-614.
Withdrawal effects of neuroleptics have not received much attention. Clozapine withdrawal phenomena have been attributed to psychosis arising from D2 supersensitivity, which is unlikely since it has minimal action on D2 receptors. The time course and clinical features of this phenomenon suggest that cholinergic overdrive and gamma-aminobutyric acid (GABA) supersensitivity occurs after withdrawal, since it is strongly anticholinergic and has a GABAergic action. Recently, a number of patients showed marked decompensation when they were switched from clozapine to risperidone, especially when they were rapidly tapered off clozapine. This was probably more due to withdrawal effects than the primary psychosis or a lack of efficacy of risperidone. A slow withdrawal schedule would facilitate homeostatic mechanisms; anticholinergics would be useful in clozapine withdrawal. This area has not received any attention from researchers, nor are there any guidelines for clinicians. This will be particularly important with the widespread use of atypical agents in the future.
Key Words: Clozapine, risperidone, substance withdrawal syndrome, neuroleptics, anticholinergics, dopamine receptors BIOL PSYCRIATRY 1996;39:135--138
Introduction The atypical neuroleptics, clozapine and risperidone have significantly improved the outlook for treating psychoses. However, as the use of these drugs widens, clinicians are facing difficulties while withdrawing patients from one group of drugs and switching them to others. This is particularly so in the case of clozapine, where it has been postulated that withdrawal is associated with a supersensitivity psychosis or rebound psychosis (Ekblom et al, From the MCP/NSH Clinical Research Center, Norristown State Hospital, Norristown, PA (CV, JD, CN) and the Medical College of PA/EPPI, Philadelphia, PA (GMS). Address reprint requests to Cherian Verghese, MD, MCP/NSH Clinical Research Center, Bldg. 52, Norristown State Hospital, Norristown, PA 19401. Received July 13, 1992; revised December 14, 1994.
© 1996 Society of Biological Psychiatry
1984; Borison et al 1988) in accordance with the hypothesis of Chouinard and Jones (1980). Data on the effects of rapid withdrawal of clozapine suggest that symptoms present within 2-3 days, usually in the first 2 weeks. Anxiety, insomnia, motor restlessness or mute withdrawal, psychotic symptoms, tardive dyskinesia, altered consciousness, confusion, nausea, and diaphoresis are reported (Simpson and Varga 1974; Simpson et al 1978; Perenyi et al 1985; Ekblom et al 1984; Alphs and Lee 1991; Eklund 1987; Borison et al 1988). The exact incidence of these symptoms is not known, although the sudden withdrawal of clozapine from the market in 1977 resulted in psychotic exacerbations in many Finnish hospitals, with one report suggesting an incidence of 39% (Kuha 1977). 0006-3223/96/$15.00 SSDI 0006-3223(95)00215-3
136
BIOLPSYCHIATRY 1996;39:135-138
Clozapine interacts with all the conventional neurotransmitters; it has less D2 affinity at clinically relevant doses, and preferentially blocks D1 (Coward et al 1989), which was confirmed with positron emission tomography (PET) studies using 11C-SCH-23390 as a ligand (Farde et al 1989). Action at D3 (Sokoloff 1990) and D4 receptors (Van Tol et al 1991) is also reported, along with 5-HTIC, 5-HT2, alpha 1 and histamine H1 receptors (Coward 1992). Its anticholinergic action is stronger than that of other neuroleptics, and is comparable to that of atropine (Snyder et al 1974). Chronic clozapine treatment increases GABA turnover in the substantia nigra, unlike typical neuroleptics, which produce the opposite effect (Marco et al 1978). We believe that many of the symptoms of acute clozapine withdrawal could be due to cholinergic overdrive, which occurs in response to its strong anticholinergic action. Dilsaver and Greden (1984) reported that the sudden withdrawal of tricyclic antidepressants, which are strongly anticholinergic, mimics the effects of the administration of cholinomimetics, which consist of (1) general somatic symptoms--a flulike syndrome (malaise, muscle aches, hot and cold flashes, sweating, anergy) and gastrointestinal symptoms (nausea, vomiting, pain, diarrhea), (2) mental symptoms--irritability, anxiety, motor overactivity or withdrawal, (3) sleep disturbances--insomnia, drowsiness, rapid eye movement rebound associated with vivid terrifying dreams, and (4) a movement disorder such as Parkinsonism. These symptoms developed within hours to 2-3 days after drug withdrawal; these symptoms were improved by atropine (Dilsaver et al 1983). The time scale for the onset of symptoms coincides with that in the reports of clozapine withdrawal. It is interesting to note that anticholinergic withdrawal does not only result in somatic symptoms. Studies done with psychotic patients under double-blind placebo-controlled conditions showed that anticholinergic withdrawal also resulted in hallucinations and psychotic symptoms in spite of continued antipsychotic coverage (Simpson et al 1965, Jellinek et al 1981). Thus the symptoms and time course of clozapine and anticholinergic withdrawal seem to be closely correlated. Supersensitivity psychosis (Chouinard 1990) is said to occur within 3 months of stopping typical neuroleptics, which is a different time scale from what is observed here. It is said to occur due to a presumed postsynaptic D2 supersensitivity after chronic D2 blockade. However, chronic clozapine treatment is not associated with increased D2 binding (O'Dell et al 1990) or D2 receptor supersensitivity (Coward 1992). Borison and colleagues (1988) argued for the presence of a supersensitivity psychosis on clozapine withdrawal. In this report, patients who underwent acute clozapine withdrawal had more
C. Verghese et al
symptoms than those who were acutely withdrawn from a chlorpromazine-benztropine combination. The authors argued that the latter combination would have as much anticholinergic action as clozapine, and since the clozapine group had more symptoms, this suggests that cholinergic mechanisms did not play a role here. However, chlorpromazine has numerous active metabolites and a very long half-life, which could have ensured a gradual tapering of anticholinergic effects. Conversely, in the clozapine group, due to the relatively short half-life of the drug, there would have been a sudden anticholinergic withdrawal, which could account for the differences in the symptoms experienced by the two groups. Various other factors may contribute to the withdrawal phenomenon, including the withdrawal effects of other neurotransmitter systems that clozapine acts on, GABA for instance. The worsening of tardive dyskinesia on clozapine withdrawal is felt to be indirect proof of dopamine supersensitivity. Chronic use of typical neuroleptics is associated with GABAergic supersensitivity in the substantia nigra (Frey et al 1987), along with a decrease in glutamic acid decarboxylase activity and GABA turnover. It is felt that these factors may be implicated in tardive dyskinesia (Gale 1980), and GABA agonists have been found to be useful in the treatment of tardive dyskinesia (Thaker et al 1990). Clozapine treatment is associated with increased GABA turnover in the substantia nigra (Marco et al 1978), and clozapine withdrawal is associated with significant GABA supersensitivity, which develops after 1 week, and returns to normal by 2 weeks (Coward et al 1989). This may account for the amelioration of tardive dyskinesia with clozapine treatment, and the worsening seen in the few weeks after withdrawal. Clinically, these data suggest that whenever possible, clozapine should be slowly tapered down, probably at the same rate at which it was tapered up. If side effects necessitate rapid withdrawal, the use of anticholinergics would help to ameliorate at least some of the symptoms. On a larger plane, the issue of withdrawing from and switching between neuroleptics is topical because the newer generation of atypical neuroleptics has a receptor profile that differs from that of typical neuroleptics and clozapine. Many of these agents have combined dopamine and serotonin blocking action, with minimal anticholinergic activity (Gerlach 1991). Clinical reports of clozapine withdrawal phenomena were reported more frequently after its reintroduction in the late 1980s. Recently, with the introduction of risperidone, a number of patients were switched from clozapine to risperidone, often with a rapid taper schedule. Many clinicians reported dramatic decompensation in some patients, often with the above-mentioned features; unfortunately some patients did not restitute as well as would be expected.
Withdrawal from Typical and Atypical Neuroleptics
The issue was not as relevant with the typical neuroleptics, many of which have overlapping profiles of action and, at the very least, they all shared D2 receptor blocking action, which was equipotent at clinically comparable doses. Consequently, it was not very important to consider the exact receptor profile of the previous neuroleptic and the one being introduced. However, this may not be so with the widespread use of atypical agents. Clozapine seems to be in a class of its own with minimal D2 action and strong affinity for all the other major neurotransmitters. Risperidone has a weaker affinity for D2 receptors than haloperidol, and blocks 5-HT2A receptors (Leysen et al 1994). Many of the antipsychotics being developed have a similar combined action on serotonin and dopamine systems. Clinicians need to be aware of the withdrawal effects of a drug when it is discontinued, and whether the new agent being introduced shares a similar receptor profile which would cover withdrawal effects. A similar situation emerged in the field of anxiolytic therapy with the introduction of buspirone (5-HT1A agonist) for the treatment of anxiety. Buspirone has no affinity for G A B A
BIOLPSYCHIATRY 1996;39:135-138
137
receptors and has no cross tolerance with the benzodiazepines; a number of patients developed serious benzodiazepine withdrawal when they were switched to buspirone. This was borne out in a placebo controlled trial (Ashton et al 1990). In these situations, a slow taper schedule, maybe over several weeks, could enable homeostatic mechanisms to restabilize. Again, a slow change over from typical to atypical agents with overlapping dosing schedules may help to avoid withdrawal reactions and psychotic flareups. We are not aware of any systematic studies or even logically evolved guidelines on the subject. Attention to these issues would help patients and clinicians and may ensure that these newer agents do not get a "bad press" in the earlier stages of their introduction.
Dr. Verghese is partially supported by a NARSAD Young Investigator Award. Dr. Simpson is partially supported by a PAL NIMH grant (MH 45190).
References Alphs LD, Lee HS (1991): Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study. J Clin Psychiatry 52:346-348. Ashton CH, Rawlins MD, Tyrer SP (1990): A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry 157:232-238. Borison RL, Diamond BI, Sinha D, Gupta RP, Prince Ajiboye A (1988): Clozapine withdrawal rebound psychosis. Psychopharmacol Bull 24:260-263. Chouinard G (1990): Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 5:21-33. Chouinard G, Jones BD (1980): Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 137:16-21. Coward DM (1992): General pharmacology of clozapine. Br J Psychiatry (supplement) 17:5-11. Coward DM, Imperato A, Urwyler S, White TG (1989): Biochemical and behavioral properties of clozapine. Psychopharmacology 99:$6-S12. Dilsaver SC, Feinberg M, Greden JF (1983): Antidepressant withdrawal symptoms treated with anticholinergic agents. Am J Psychiatry 140:249-251. Dilsaver SC, Greden JF (1984): Antidepressant withdrawal phenomena. Biol Psychiatry 19:237-256. Ekblom B, Eriksson K, Lindstrom LH (1984): Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology 83:293-294. Eklund K (1987): Supersensitivity and clozapine withdrawal. Psychopharmacology 91:135.
Farde L, Wiesel F-A, Nordstrom A-L, Sedvall G (1989): D1 and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99:$28-$31. Frey JM, Ticku MK, Hoffman RD (1987): GABAergic supersensitivity within the pars reticulata of the rat substantia nigra following chronic haloperidol administration. Brain Res 425: 73- 84. Gale K (1980): Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature 283:569-570. Gerlach J (1991): New antipsychotics: Classification, efficacy, and adverse effects. Schizophr Bull 17:289-309. Jellinek T, Gardos G, Cole J (1981): Adverse effects of antiparkinson drug withdrawal. Am J Psychiatry 138:1567-1571. Kuha S (1977): The consequences of sudden stopping of clozapine in Finland. In Vlth World Congress of Psychiatry, Honolulu, Am Psychiatr Assoc Abstracts 813:153. Leysen JE, Janssen PM, Megens AA, Schotte A (1994): Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry 55(suppl):5-12. Marco E, Mao CC, Revuelata A, Peralta E, Costa E (1978): Turnover rates of gamma-aminobutyric acid in substantia nigra, N. caudatus, globus pallidus and N. accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics. Neuropharmacology 17:589-596. O'Dell SJ, La Hoste GJ, Widmark CB, Shapiro RM, Potldn SG, Marshall JF (1990): Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse 6:146-153. Perenyi A, Kuncz E, Bagdy G (1985): Early relapse after sudden
138
BIOL PSYCHIATRY 1996;39:135-138
withdrawal or dose reduction of clozapine. Psychopharmacology 86:244. Simpson GM, Amin M, Kunz E (1965): Withdrawal effects of phenothiazines. Compr Psychiatry 6:347-351. Simpson GM, Lee JH, Shrivastava RK (1978): Clozapine in tardive dyskinesia. Psychopharmacology 56:75-80. Simpson GM, Varga E (1974): CIozapine--A new antipsychotic agent. Curt Ther Res 16:679-686. Snyder S, Greenberg D, Yamamura HI (1974): Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 31:58-61. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC
C. Verghese et al
(1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146-151. Thaker GK, Nguyen JA, Strauss ME, Jocobson T, Kaup BA, Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146-151. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991): Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610-614.