ATYPICAL ANTIPSYCHOTICATYPICAL ANTIPSYCHOTIC

CLOZAPINECLOZAPINEBY: PATRIZIA

ORLANDO

CLOZAPINECLOZAPINE

Clozapine is a second Clozapine is a second generation/atypical antipsychotic.generation/atypical antipsychotic.

Trade name is ClozarilTrade name is Clozaril

                 

 

               

 

HISTORY OF HISTORY OF ANTIPSYCHOTICSANTIPSYCHOTICS

Anti-psychotics were discovered accidentally by a Anti-psychotics were discovered accidentally by a French naval surgeon, Henri Laborit. Laborit was French naval surgeon, Henri Laborit. Laborit was interested in circulatory shock, not schizophrenia.interested in circulatory shock, not schizophrenia.

Laborit experimented with a variety of drugs to Laborit experimented with a variety of drugs to combat shock syndrome. combat shock syndrome.

One of the drugs was an agent called One of the drugs was an agent called Pomethazine. His primary reason for using the Pomethazine. His primary reason for using the drug was for its effects on the ANS, however, he drug was for its effects on the ANS, however, he discovered the secondary properties of the drugdiscovered the secondary properties of the drug The drug made patients drowsy, reduced pain, The drug made patients drowsy, reduced pain,

and created a feeling of euphoric quietude.” and created a feeling of euphoric quietude.” This drug has psychological effects.This drug has psychological effects.

Laborit’s observation were used to modify the Laborit’s observation were used to modify the formula of Promethazine into the first effective formula of Promethazine into the first effective anti-psychotic medication, Chloropromazine anti-psychotic medication, Chloropromazine (Thorazine).(Thorazine).

Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.Oxford University Press: New York.

Side Effects of Typical Side Effects of Typical AntipsychoticsAntipsychotics

Extrapyramidal Symptoms (EPS): Typical Extrapyramidal Symptoms (EPS): Typical antipsychotics effect the extrapyramidal tract by antipsychotics effect the extrapyramidal tract by blocking post-synaptic receptors in the basal ganglia. blocking post-synaptic receptors in the basal ganglia. Chief among the acute side effects are motor Chief among the acute side effects are motor disturbances, which gives the appearance of disturbances, which gives the appearance of Parkinsonism.Parkinsonism. Dyskinesia: disordered movements Dyskinesia: disordered movements Akinesia: slowness of movement and underactivityAkinesia: slowness of movement and underactivity Tardive Dyskinesia: repetative unvoluntary movement of the Tardive Dyskinesia: repetative unvoluntary movement of the

mouth and tongue ( often in the form of a lip smacking), mouth and tongue ( often in the form of a lip smacking), trunk, and extremities.trunk, and extremities.

(30-50% of patients experience these side effects while on (30-50% of patients experience these side effects while on typical antipsychotic medication.)typical antipsychotic medication.)

Negative Symptoms: typical antipsychotics seemed to Negative Symptoms: typical antipsychotics seemed to have little to no improvement in negative symptoms.have little to no improvement in negative symptoms.

ARRIVAL OF THE ATYPICAL ARRIVAL OF THE ATYPICAL ANTIPSYCHOTICANTIPSYCHOTIC

““German psychiatrists working with G. Stille German psychiatrists working with G. Stille at Wander Pharmaceuticals in Bern, at Wander Pharmaceuticals in Bern, Switzerland, in the early 1960s worked to Switzerland, in the early 1960s worked to refute that EPS and antipsychotic efficacy refute that EPS and antipsychotic efficacy were linked. Their work led to the were linked. Their work led to the introduction of Clozapine, an antipsychotic introduction of Clozapine, an antipsychotic with no EPS.”with no EPS.”

Clozapine was briefly marketed and quickly Clozapine was briefly marketed and quickly withdrawn for two reasons:withdrawn for two reasons: The embarrassment of not having any EPS, andThe embarrassment of not having any EPS, and AgranulocytosisAgranulocytosis

Side Effects of ClozapineSide Effects of Clozapine Major side effect: Major side effect:

AgranulocytosisAgranulocytosis: a destructive condition in which : a destructive condition in which the bone marrow stops producing white blood cell, the bone marrow stops producing white blood cell, thus making the patient susceptible to infection.thus making the patient susceptible to infection.

Clozapine may cause many side effects. The following Clozapine may cause many side effects. The following side effects are grouped by the body system affected:side effects are grouped by the body system affected: CardiovascularCardiovascular: decreases of blood pressure which : decreases of blood pressure which

may cause dizziness or fainting; rapid heart rate, may cause dizziness or fainting; rapid heart rate, changes in heart rhythm and electrocardiogram. changes in heart rhythm and electrocardiogram.

Nervous systemNervous system: sedation, increased seizure : sedation, increased seizure tendency. tendency.

Digestive systemDigestive system: increased appetite (weight gain), : increased appetite (weight gain), excessive salivation, nausea, constipation, abnormal excessive salivation, nausea, constipation, abnormal liver tests, elevated blood sugar. liver tests, elevated blood sugar.

AutonomicAutonomic: blurred vision, exacerbation of glaucoma, : blurred vision, exacerbation of glaucoma, dry mouth, nasal congestion, decreased sweatingdry mouth, nasal congestion, decreased sweating

SkinSkin: rashes: rashes http://www.minddisorders.com/Br-Del/Clozapine.html http://www.minddisorders.com/Br-Del/Clozapine.html

STUDY 1STUDY 1A Double-Blind Comparative Study of Clozapine and A Double-Blind Comparative Study of Clozapine and Risperidone in the Management of Severe Chronic Risperidone in the Management of Severe Chronic

SchizophreniaSchizophreniaBy: Azorin, J. M. et al.By: Azorin, J. M. et al.

Type of studyType of study: Double-blind comparative study: Double-blind comparative study PopulationPopulation: Male and female patients aged 18-65 : Male and female patients aged 18-65

years who met the DSM-IV criteria for schizophrenia years who met the DSM-IV criteria for schizophrenia and study requirements for poor previous treatment and study requirements for poor previous treatment response.response.

PatientsPatients:Total of 273 patients were randomly assigned :Total of 273 patients were randomly assigned to one of the two groups, and 201 patients completed to one of the two groups, and 201 patients completed the study. Reasons for leaving the study included the study. Reasons for leaving the study included adverse event, consent withdrawal, protocol violation, adverse event, consent withdrawal, protocol violation, treatment failure, and death (unrelated to therapy).treatment failure, and death (unrelated to therapy).

ResultsResults:: Magnitude of the response (determined by BPRS and CGI Magnitude of the response (determined by BPRS and CGI

scores) was significantly greater in the Clozapine group.scores) was significantly greater in the Clozapine group. Clozapine exhibited clear therapeutic superiority over Clozapine exhibited clear therapeutic superiority over

Risperidone for the majority of the efficacy measures.Risperidone for the majority of the efficacy measures. LimitationsLimitations::

Significant difference in the dosage amount between the Significant difference in the dosage amount between the groups which could exert some explanation for the difference groups which could exert some explanation for the difference in efficacy.in efficacy.

STUDY 2STUDY 2Positive and Negative Symptom Response to Clozapine in Positive and Negative Symptom Response to Clozapine in

Schizophrenic Patients With and Without the Deficit SyndromeSchizophrenic Patients With and Without the Deficit SyndromeBy: Buchanan, R. W. et al.By: Buchanan, R. W. et al.

Type of studyType of study: 10 week Double-blind, parallel-groups : 10 week Double-blind, parallel-groups comparison of Clozapine and Haloperidolcomparison of Clozapine and Haloperidol

PopulationPopulation: Male and female patients that meet the DSM-III-R : Male and female patients that meet the DSM-III-R criteria for schizophrenia or schizoaffective disorder who also criteria for schizophrenia or schizoaffective disorder who also had residual (+) and (-) symptoms after previous treatment.had residual (+) and (-) symptoms after previous treatment.

PatientsPatients: 64 of the 75 patients completed the study. Reasons : 64 of the 75 patients completed the study. Reasons for drop out was for noncompliance, relapse, and low RBC for drop out was for noncompliance, relapse, and low RBC count, seizures, and withdrawal of consent.count, seizures, and withdrawal of consent.

ResultsResults:: For patients that completed the 10 week double blind study, For patients that completed the 10 week double blind study,

Clozapine was superior to Haloperidol in treating positive Clozapine was superior to Haloperidol in treating positive symptoms, however, there was no long term effect of Clozapine symptoms, however, there was no long term effect of Clozapine on primary or secondary negative symptoms. on primary or secondary negative symptoms.

Patients receiving Haloperidol worsened in Anhedonia Patients receiving Haloperidol worsened in Anhedonia significantly.significantly.

LimitationsLimitations Patients used were not limited solely to those diagnosed with Patients used were not limited solely to those diagnosed with

schizophreniaschizophrenia Sample size was smallSample size was small

STUDY 3STUDY 3The safety of clozapine in the treatment of first- and multiple-The safety of clozapine in the treatment of first- and multiple-

episode patients with treatment-resistant schizophreniaepisode patients with treatment-resistant schizophreniaBy: Hofer, A. et al.By: Hofer, A. et al.

Population:Population: Contrasted first and multiple episode male and female patients with Contrasted first and multiple episode male and female patients with

schizophrenia on Clozapine.schizophrenia on Clozapine. Patients:Patients:

39 first-episode patients and 56 multiple-episode patients who were 39 first-episode patients and 56 multiple-episode patients who were resistant to other treatments. Only 52 of the 95 patients completed the resistant to other treatments. Only 52 of the 95 patients completed the study. Reasons for premature termination was admission to a secure study. Reasons for premature termination was admission to a secure unit, side-effects, non-compliance, and logistic reasons.unit, side-effects, non-compliance, and logistic reasons.

Results: Results: No significant difference in side effects between the groups.No significant difference in side effects between the groups. Response and side effects to Clozapine treatment do not seem to be Response and side effects to Clozapine treatment do not seem to be

determined by the chronicity of the disorder.determined by the chronicity of the disorder. Negative association between age and response rate. The mean age of Negative association between age and response rate. The mean age of

responders was 26.2 +/- 9 years, compared to 31.1 +/- 9.9 years of responders was 26.2 +/- 9 years, compared to 31.1 +/- 9.9 years of non responders.non responders.

Limitations:Limitations: Large number of unexpected drop-outs related to geographical Large number of unexpected drop-outs related to geographical

distribution of patients.distribution of patients. Dosages of Clozapine are seen to be lower than in the average study. Dosages of Clozapine are seen to be lower than in the average study.

263.5mg/d in this study in comparison to 600mg/d.263.5mg/d in this study in comparison to 600mg/d.

Dosages and Treatment Dosages and Treatment LengthLength

The regular dosage given to patients is The regular dosage given to patients is approximately 600mg per day.approximately 600mg per day.

To minimize side effects, the initial dose of To minimize side effects, the initial dose of Clozapine may start of low and progressively Clozapine may start of low and progressively increase to 200mg taken three times per day.increase to 200mg taken three times per day.

Clozapine is not a cure for schizophrenia, rather, it Clozapine is not a cure for schizophrenia, rather, it is used to relieve the symptoms of the disease. is used to relieve the symptoms of the disease. Therefore, the use of anti-psychotics is life-long to Therefore, the use of anti-psychotics is life-long to ensure that the symptoms are controlled.ensure that the symptoms are controlled.

The patient may decide to discontinue the use of The patient may decide to discontinue the use of Clozapine due to its side effects and is usually Clozapine due to its side effects and is usually placed on a less potent antipsychotic.placed on a less potent antipsychotic.

The discontinuation of all anti-psychotics will cause The discontinuation of all anti-psychotics will cause a relapse of positive and negative symptoms.a relapse of positive and negative symptoms.

BRAIN AREAS INVOLVED IN BRAIN AREAS INVOLVED IN ANTIPSYCHOTIC TREATMENTANTIPSYCHOTIC TREATMENT

The oversimplified version of what brain areas The oversimplified version of what brain areas are involved in anti-psychotic medication use is:are involved in anti-psychotic medication use is: Reticular Activating SystemReticular Activating System: the effects on this area : the effects on this area

generally moderate spontaneous activity and generally moderate spontaneous activity and decrease the patients reactivity to stimuli.decrease the patients reactivity to stimuli.

The Limbic SystemThe Limbic System: the effects on this area generally : the effects on this area generally serves to moderate or blunt emotional arousal.serves to moderate or blunt emotional arousal.

The HypothalamusThe Hypothalamus: the effects on this areas : the effects on this areas generally serve to modulate metabolism, alertness, generally serve to modulate metabolism, alertness, and muscle tone.and muscle tone.

Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4thth Ed. Wadsworth: Ed. Wadsworth: USA.USA.

BRAIN AREAS INVOLVED IN SCHIZOPHRENIA BRAIN AREAS INVOLVED IN SCHIZOPHRENIA 4 DOPAMINE PATHWAYS4 DOPAMINE PATHWAYS

There are four dopamine pathways in the brain:There are four dopamine pathways in the brain:1.1. Nigrostriatal Dopamine TractNigrostriatal Dopamine Tract

Ascends from the substantia nigra to the neostriatum, Ascends from the substantia nigra to the neostriatum, which is part of the basal ganglia.which is part of the basal ganglia.

2.2. Mesolimbic PathwayMesolimbic Pathway Ascends from the VTA of the midbrain to the Nucleus Ascends from the VTA of the midbrain to the Nucleus

Accumbens, septum and amygdala.Accumbens, septum and amygdala.3.3. Mesocortical TractMesocortical Tract

Ascends from the VTA to the prefrontal cortex, cingulate Ascends from the VTA to the prefrontal cortex, cingulate gyrus, and premotor area.gyrus, and premotor area.

4.4. Hypothalamic-Pituitary PathwayHypothalamic-Pituitary Pathway Occur in the hypothalamus and extend to the pituitary Occur in the hypothalamus and extend to the pituitary

glandgland

Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.Oxford University Press: New York.

NEUROBIOLOGY OF TYPICAL NEUROBIOLOGY OF TYPICAL ANTIPSYCHOTICSANTIPSYCHOTICS

The Dopamine HypothesisThe Dopamine Hypothesis “ “ It is believed that although antipsychotic It is believed that although antipsychotic

medication block norepinephrine, serotonin, and medication block norepinephrine, serotonin, and acetylcholine, their primary action is as central acetylcholine, their primary action is as central dopamine antagonists. That is, these drugs block dopamine antagonists. That is, these drugs block central dopamine receptors, particularly the Dcentral dopamine receptors, particularly the D22 subtype, and thus inhibit dopaminergic subtype, and thus inhibit dopaminergic neurotransmission in the brain. The postsynaptic neurotransmission in the brain. The postsynaptic receptor blockade in the limbic system is receptor blockade in the limbic system is thought to reduce the schizophrenic symptoms.” thought to reduce the schizophrenic symptoms.”

Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4thth Ed. Ed. Wadsworth: USA.Wadsworth: USA.

NEUROBIOLOGY OF NEUROBIOLOGY OF CLOZAPINECLOZAPINE

All schizophrenic patients do not respond to All schizophrenic patients do not respond to antipsychotics that have an affinity for DA Dantipsychotics that have an affinity for DA D2 2 receptors. This has lead researchers to believe receptors. This has lead researchers to believe that there are other Dopamine receptors that that there are other Dopamine receptors that may contribute to the cause of schizophrenia. may contribute to the cause of schizophrenia.

The DA DThe DA D44 subtype has also been implicated in subtype has also been implicated in the illness.the illness.

The DA DThe DA D44 is of special interest because of its is of special interest because of its concentration in the hippocampus and the concentration in the hippocampus and the cerebral cortex. It is through the Dcerebral cortex. It is through the D22 and the D and the D44 receptors that Clozapine exerts its affects.receptors that Clozapine exerts its affects.

Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.Neuroscience. Oxford University Press: New York.

NEUROBIOLOGY OF NEUROBIOLOGY OF CLOZAPINECLOZAPINE

Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D4 receptor subtype.

Mechanism of ActionMechanism of Action

The exact mechanism of action unknown, however, The exact mechanism of action unknown, however, it is believed that Clozapine selectively antagonizes it is believed that Clozapine selectively antagonizes dopamine D1 and D4 receptors, serotonin 5-HT2 dopamine D1 and D4 receptors, serotonin 5-HT2 receptors and others.receptors and others.

Atypical antipsychotics, like Clozapine, are Atypical antipsychotics, like Clozapine, are distinguished by their relatively low affinity for the distinguished by their relatively low affinity for the DA DDA D22 receptor subtype and its high affinity for the receptor subtype and its high affinity for the DA DDA D44 receptor subtype and the 5-HT receptor subtype and the 5-HT22 receptor receptor subtype.subtype.

Clozapine may be able to permit more normal Clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions mesostriatal, mesolimbic and mesocortical regions

Mechanism of ActionMechanism of Action Atypical antipsychoticsAtypical antipsychotics (serotonin-dopamine (serotonin-dopamine

antagonists) are antagonists of D2 and serotonin 2A antagonists) are antagonists of D2 and serotonin 2A receptors, but they can affect many other types of receptors, but they can affect many other types of receptors. receptors.

Atypical antipsychotics: Atypical antipsychotics:  D2 receptor blockade of postsynaptic in the D2 receptor blockade of postsynaptic in the

mesolimbic pathway mesolimbic pathway reduce positive symptomsreduce positive symptoms enhanced dopamine release and 5-HT2A receptor enhanced dopamine release and 5-HT2A receptor

blockade in the mesocortical pathway blockade in the mesocortical pathway reduce reduce negative symptomsnegative symptoms

other receptor-binding properties may contribute to other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophreniasymptoms and depression in schizophrenia

CLOZAPINECLOZAPINE

Clozapine is considered by Clozapine is considered by many as the only atypical many as the only atypical antipsychotic due to its antipsychotic due to its elevated effects over other elevated effects over other “atypical” antipsychotics.“atypical” antipsychotics.

Patients do not experience Patients do not experience extrapyramidal symptoms extrapyramidal symptoms (EPS)(EPS)

Used for treatment-Used for treatment-resistant patients that resistant patients that have not responded to any have not responded to any other medication.other medication.

Has been shown to have Has been shown to have some effectiveness in the some effectiveness in the treatment of negative treatment of negative symptoms.symptoms.

There is a high correlation There is a high correlation between patients who take between patients who take this medication and the this medication and the development of development of Agranulocytosis.Agranulocytosis.

Clozapine costs more than Clozapine costs more than typical anti-psychotics, typical anti-psychotics, however, the cost is however, the cost is relatively the same for relatively the same for atypical antipsychoticsatypical antipsychotics

The effective dose of The effective dose of Clozapine is higher than Clozapine is higher than other atypical antipsychotics. other atypical antipsychotics.

Tends to work more Tends to work more effectively in younger effectively in younger patients (20s) than older patients (20s) than older patients (30s).patients (30s).

ADVANTAGES DISADVANTAGES

CONCLUSIONSCONCLUSIONS

Is there any controversy involved in using this Is there any controversy involved in using this treatment?treatment? There is some controversy surrounding this drug.There is some controversy surrounding this drug. The debate is over when this drug should be used. Many The debate is over when this drug should be used. Many

say that due to the increased risk of attaining say that due to the increased risk of attaining Agranulocytosis (which can be fatal is not detected) this Agranulocytosis (which can be fatal is not detected) this drug should be used only if the individual is un drug should be used only if the individual is un responsive to other drugs. However, there has been responsive to other drugs. However, there has been findings that Clozapine is significantly more affective if findings that Clozapine is significantly more affective if administered to the patient at a younger age. administered to the patient at a younger age.

Is this treatment appropriate for every patient?Is this treatment appropriate for every patient? NoNo Typically Clozapine is used on schizophrenic patients Typically Clozapine is used on schizophrenic patients

that are treatment-refractory or unresponsive to other that are treatment-refractory or unresponsive to other medications.medications.

ConclusionsConclusions What future directions would be necessary to show how the What future directions would be necessary to show how the

therapeutic intervention impacts on neurobiology?therapeutic intervention impacts on neurobiology? The cause of schizophrenia is still unknown. To understand The cause of schizophrenia is still unknown. To understand

how medications for the treatment of schizophrenia work, we how medications for the treatment of schizophrenia work, we must first fully understand the neurobiology of the illness. must first fully understand the neurobiology of the illness.

Therefore, further research should be done on the Therefore, further research should be done on the neurobiology of the illness itself, as well as the secondary neurobiology of the illness itself, as well as the secondary neurotransmitters that are altered after Dopamine receptors neurotransmitters that are altered after Dopamine receptors have been altered by the anti-psychotics medication.have been altered by the anti-psychotics medication.

Overall OpinionOverall Opinion My overall opinion of this treatment is in favour of the use of My overall opinion of this treatment is in favour of the use of

Clozapine for treatment-resistant schizophrenic patients. I Clozapine for treatment-resistant schizophrenic patients. I believe that other atypicals should be the primary treatment of believe that other atypicals should be the primary treatment of schizophrenics to reduce negative side effects from the schizophrenics to reduce negative side effects from the medication.medication.

If such treatment has no effect, doctors should be hasty in If such treatment has no effect, doctors should be hasty in switching patients to Clozapine because of the noted efficacy switching patients to Clozapine because of the noted efficacy of the drug in younger patients.of the drug in younger patients.

Although the drug has many advantages, it is not without its Although the drug has many advantages, it is not without its disadvantages and patients on Clozapine should be monitored disadvantages and patients on Clozapine should be monitored for severe side effects, especially that of Agranulocytosis.for severe side effects, especially that of Agranulocytosis.

Works CitedWorks Cited

Azorin, J. , Spiegel, R., Remington, G., Vanelle, J., Pere, J., iguere, M., & Bourdeix, I. (2001). A Double-Blind Comparitive Azorin, J. , Spiegel, R., Remington, G., Vanelle, J., Pere, J., iguere, M., & Bourdeix, I. (2001). A Double-Blind Comparitive Study of Clozapine and Risperidone in the Management of Severe Chronic Schizophrenia. Study of Clozapine and Risperidone in the Management of Severe Chronic Schizophrenia. Am J PsychiatryAm J Psychiatry,, 158, 158, 1305- 1305-1313.1313.

Belmaker, R. H. (2003). Mechanism of atypicality of antipsychotic drugs. Belmaker, R. H. (2003). Mechanism of atypicality of antipsychotic drugs. Progress in Neuro-Psychopharmacology & Progress in Neuro-Psychopharmacology & Biological PsychiatryBiological Psychiatry, , 2727, 1067-1069. , 1067-1069.

Buchanan, R. W., Breier, A., Kirkpatrick, B., Ball, P., & Carpenter, W. T. (1998). Positive and Negative Symptom Response Buchanan, R. W., Breier, A., Kirkpatrick, B., Ball, P., & Carpenter, W. T. (1998). Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome. to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome. Am J PsychiatryAm J Psychiatry, , 155,155, 751-760. 751-760.

Heinrichs, R. W., (2001). Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and NeuroscienceIn Search of Madness: Schizophrenia and Neuroscience . Oxford University Press: New York.. Oxford University Press: New York.

Hofer, A., Hummer, M., Kemmler, G., Kurz, M., Kurzthaler, I., & Fleischhacker, W. W. (2003). The safety of clozapine in the Hofer, A., Hummer, M., Kemmler, G., Kurz, M., Kurzthaler, I., & Fleischhacker, W. W. (2003). The safety of clozapine in the treatment of first- and multiple-episode patients with treatment-resistant schizophrenia. treatment of first- and multiple-episode patients with treatment-resistant schizophrenia. International Journal of International Journal of NeuropsychopharmacologyNeuropsychopharmacology, , 66, 201-206., 201-206.

Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4Drug Use and Abuse 4thth Ed Ed. Wadsworth: USA.. Wadsworth: USA.

Shen, Winston. W., (1999). A History of Antipsychotic Drug Development. Shen, Winston. W., (1999). A History of Antipsychotic Drug Development. Comprehensive PsychiatryComprehensive Psychiatry, , 4040 (6), 407-414. (6), 407-414.

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