ATYPICAL ANTIPSYCHOTIC CLOZAPINE BY: PATRIZIA ORLANDO

CLOZAPINE Clozapine is a second generation/atypical antipsychotic. Clozapine is a second generation/atypical antipsychotic. Trade name is Clozaril Trade name is Clozaril

HISTORY OF ANTIPSYCHOTICS Anti-psychotics were discovered accidentally by a French naval surgeon, Henri Laborit. Laborit was interested in circulatory shock, not schizophrenia. Anti-psychotics were discovered accidentally by a French naval surgeon, Henri Laborit. Laborit was interested in circulatory shock, not schizophrenia. Laborit experimented with a variety of drugs to combat shock syndrome. Laborit experimented with a variety of drugs to combat shock syndrome. One of the drugs was an agent called Pomethazine. His primary reason for using the drug was for its effects on the ANS, however, he discovered the secondary properties of the drug One of the drugs was an agent called Pomethazine. His primary reason for using the drug was for its effects on the ANS, however, he discovered the secondary properties of the drug The drug made patients drowsy, reduced pain, and created a feeling of euphoric quietude.” This drug has psychological effects. The drug made patients drowsy, reduced pain, and created a feeling of euphoric quietude.” This drug has psychological effects. Laborit’s observation were used to modify the formula of Promethazine into the first effective anti-psychotic medication, Chloropromazine (Thorazine). Laborit’s observation were used to modify the formula of Promethazine into the first effective anti-psychotic medication, Chloropromazine (Thorazine). Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.

Side Effects of Typical Antipsychotics Extrapyramidal Symptoms (EPS): Typical antipsychotics effect the extrapyramidal tract by blocking post-synaptic receptors in the basal ganglia. Chief among the acute side effects are motor disturbances, which gives the appearance of Parkinsonism. Extrapyramidal Symptoms (EPS): Typical antipsychotics effect the extrapyramidal tract by blocking post-synaptic receptors in the basal ganglia. Chief among the acute side effects are motor disturbances, which gives the appearance of Parkinsonism. Dyskinesia: disordered movements Dyskinesia: disordered movements Akinesia: slowness of movement and underactivity Akinesia: slowness of movement and underactivity Tardive Dyskinesia: repetative unvoluntary movement of the mouth and tongue ( often in the form of a lip smacking), trunk, and extremities. Tardive Dyskinesia: repetative unvoluntary movement of the mouth and tongue ( often in the form of a lip smacking), trunk, and extremities. (30-50% of patients experience these side effects while on typical antipsychotic medication.) (30-50% of patients experience these side effects while on typical antipsychotic medication.) Negative Symptoms: typical antipsychotics seemed to have little to no improvement in negative symptoms. Negative Symptoms: typical antipsychotics seemed to have little to no improvement in negative symptoms.

ARRIVAL OF THE ATYPICAL ANTIPSYCHOTIC “German psychiatrists working with G. Stille at Wander Pharmaceuticals in Bern, Switzerland, in the early 1960s worked to refute that EPS and antipsychotic efficacy were linked. Their work led to the introduction of Clozapine, an antipsychotic with no EPS.” “German psychiatrists working with G. Stille at Wander Pharmaceuticals in Bern, Switzerland, in the early 1960s worked to refute that EPS and antipsychotic efficacy were linked. Their work led to the introduction of Clozapine, an antipsychotic with no EPS.” Clozapine was briefly marketed and quickly withdrawn for two reasons: Clozapine was briefly marketed and quickly withdrawn for two reasons: The embarrassment of not having any EPS, and The embarrassment of not having any EPS, and Agranulocytosis Agranulocytosis

Side Effects of Clozapine Major side effect: Major side effect: Agranulocytosis: a destructive condition in which the bone marrow stops producing white blood cell, thus making the patient susceptible to infection. Agranulocytosis: a destructive condition in which the bone marrow stops producing white blood cell, thus making the patient susceptible to infection. Clozapine may cause many side effects. The following side effects are grouped by the body system affected: Clozapine may cause many side effects. The following side effects are grouped by the body system affected: Cardiovascular: decreases of blood pressure which may cause dizziness or fainting; rapid heart rate, changes in heart rhythm and electrocardiogram. Cardiovascular: decreases of blood pressure which may cause dizziness or fainting; rapid heart rate, changes in heart rhythm and electrocardiogram. Nervous system: sedation, increased seizure tendency. Nervous system: sedation, increased seizure tendency. Digestive system: increased appetite (weight gain), excessive salivation, nausea, constipation, abnormal liver tests, elevated blood sugar. Digestive system: increased appetite (weight gain), excessive salivation, nausea, constipation, abnormal liver tests, elevated blood sugar. Autonomic: blurred vision, exacerbation of glaucoma, dry mouth, nasal congestion, decreased sweating Autonomic: blurred vision, exacerbation of glaucoma, dry mouth, nasal congestion, decreased sweating Skin: rashes Skin: rashes

STUDY 1 A Double-Blind Comparative Study of Clozapine and Risperidone in the Management of Severe Chronic Schizophrenia By: Azorin, J. M. et al. Type of study: Double-blind comparative study Type of study: Double-blind comparative study Population: Male and female patients aged years who met the DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response. Population: Male and female patients aged years who met the DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response. Patients:Total of 273 patients were randomly assigned to one of the two groups, and 201 patients completed the study. Reasons for leaving the study included adverse event, consent withdrawal, protocol violation, treatment failure, and death (unrelated to therapy). Patients:Total of 273 patients were randomly assigned to one of the two groups, and 201 patients completed the study. Reasons for leaving the study included adverse event, consent withdrawal, protocol violation, treatment failure, and death (unrelated to therapy). Results: Results: Magnitude of the response (determined by BPRS and CGI scores) was significantly greater in the Clozapine group. Magnitude of the response (determined by BPRS and CGI scores) was significantly greater in the Clozapine group. Clozapine exhibited clear therapeutic superiority over Risperidone for the majority of the efficacy measures. Clozapine exhibited clear therapeutic superiority over Risperidone for the majority of the efficacy measures. Limitations: Limitations: Significant difference in the dosage amount between the groups which could exert some explanation for the difference in efficacy. Significant difference in the dosage amount between the groups which could exert some explanation for the difference in efficacy.

STUDY 2 Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome By: Buchanan, R. W. et al. Type of study: 10 week Double-blind, parallel-groups comparison of Clozapine and Haloperidol Type of study: 10 week Double-blind, parallel-groups comparison of Clozapine and Haloperidol Population: Male and female patients that meet the DSM-III-R criteria for schizophrenia or schizoaffective disorder who also had residual (+) and (-) symptoms after previous treatment. Population: Male and female patients that meet the DSM-III-R criteria for schizophrenia or schizoaffective disorder who also had residual (+) and (-) symptoms after previous treatment. Patients: 64 of the 75 patients completed the study. Reasons for drop out was for noncompliance, relapse, and low RBC count, seizures, and withdrawal of consent. Patients: 64 of the 75 patients completed the study. Reasons for drop out was for noncompliance, relapse, and low RBC count, seizures, and withdrawal of consent. Results: Results: For patients that completed the 10 week double blind study, Clozapine was superior to Haloperidol in treating positive symptoms, however, there was no long term effect of Clozapine on primary or secondary negative symptoms. For patients that completed the 10 week double blind study, Clozapine was superior to Haloperidol in treating positive symptoms, however, there was no long term effect of Clozapine on primary or secondary negative symptoms. Patients receiving Haloperidol worsened in Anhedonia significantly. Patients receiving Haloperidol worsened in Anhedonia significantly. Limitations Limitations Patients used were not limited solely to those diagnosed with schizophrenia Patients used were not limited solely to those diagnosed with schizophrenia Sample size was small Sample size was small

STUDY 3 The safety of clozapine in the treatment of first- and multiple-episode patients with treatment-resistant schizophrenia By: Hofer, A. et al. Population: Population: Contrasted first and multiple episode male and female patients with schizophrenia on Clozapine. Contrasted first and multiple episode male and female patients with schizophrenia on Clozapine. Patients: Patients: 39 first-episode patients and 56 multiple-episode patients who were resistant to other treatments. Only 52 of the 95 patients completed the study. Reasons for premature termination was admission to a secure unit, side-effects, non- compliance, and logistic reasons. 39 first-episode patients and 56 multiple-episode patients who were resistant to other treatments. Only 52 of the 95 patients completed the study. Reasons for premature termination was admission to a secure 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 determined by the chronicity of the disorder. Response and side effects to Clozapine treatment do not seem to be determined by the chronicity of the disorder. Negative association between age and response rate. The mean age of responders was /- 9 years, compared to /- 9.9 years of non responders. Negative association between age and response rate. The mean age of responders was /- 9 years, compared to /- 9.9 years of non responders. Limitations: Limitations: Large number of unexpected drop-outs related to geographical distribution of patients. Large number of unexpected drop-outs related to geographical distribution of patients. Dosages of Clozapine are seen to be lower than in the average study mg/d in this study in comparison to 600mg/d. Dosages of Clozapine are seen to be lower than in the average study mg/d in this study in comparison to 600mg/d.

Dosages and Treatment Length The regular dosage given to patients is approximately 600mg per day. The regular dosage given to patients is approximately 600mg per day. To minimize side effects, the initial dose of Clozapine may start of low and progressively increase to 200mg taken three times per day. To minimize side effects, the initial dose of Clozapine may start of low and progressively increase to 200mg taken three times per day. Clozapine is not a cure for schizophrenia, rather, it is used to relieve the symptoms of the disease. Therefore, the use of anti-psychotics is life-long to ensure that the symptoms are controlled. Clozapine is not a cure for schizophrenia, rather, it is used to relieve the symptoms of the disease. Therefore, the use of anti-psychotics is life-long to ensure that the symptoms are controlled. The patient may decide to discontinue the use of Clozapine due to its side effects and is usually placed on a less potent antipsychotic. The patient may decide to discontinue the use of Clozapine due to its side effects and is usually placed on a less potent antipsychotic. The discontinuation of all anti-psychotics will cause a relapse of positive and negative symptoms. The discontinuation of all anti-psychotics will cause a relapse of positive and negative symptoms.

BRAIN AREAS INVOLVED IN ANTIPSYCHOTIC TREATMENT The oversimplified version of what brain areas are involved in anti-psychotic medication use is: The oversimplified version of what brain areas are involved in anti-psychotic medication use is: Reticular Activating System: the effects on this area generally moderate spontaneous activity and decrease the patients reactivity to stimuli. Reticular Activating System: the effects on this area generally moderate spontaneous activity and decrease the patients reactivity to stimuli. The Limbic System: the effects on this area generally serves to moderate or blunt emotional arousal. The Limbic System: the effects on this area generally serves to moderate or blunt emotional arousal. The Hypothalamus: the effects on this areas generally serve to modulate metabolism, alertness, and muscle tone. The Hypothalamus: the effects on this areas generally serve to modulate metabolism, alertness, and muscle tone. Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4 th Ed. Wadsworth: USA. Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4 th Ed. Wadsworth: USA.

BRAIN AREAS INVOLVED IN SCHIZOPHRENIA 4 DOPAMINE PATHWAYS There are four dopamine pathways in the brain: 1. Nigrostriatal Dopamine Tract Ascends from the substantia nigra to the neostriatum, which is part of the basal ganglia. Ascends from the substantia nigra to the neostriatum, which is part of the basal ganglia. 2. Mesolimbic Pathway Ascends from the VTA of the midbrain to the Nucleus Accumbens, septum and amygdala. Ascends from the VTA of the midbrain to the Nucleus Accumbens, septum and amygdala. 3. Mesocortical Tract Ascends from the VTA to the prefrontal cortex, cingulate gyrus, and premotor area. Ascends from the VTA to the prefrontal cortex, cingulate gyrus, and premotor area. 4. Hypothalamic-Pituitary Pathway Occur in the hypothalamus and extend to the pituitary gland Occur in the hypothalamus and extend to the pituitary gland Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.

NEUROBIOLOGY OF TYPICAL ANTIPSYCHOTICS The Dopamine Hypothesis The Dopamine Hypothesis “ It is believed that although antipsychotic medication block norepinephrine, serotonin, and acetylcholine, their primary action is as central dopamine antagonists. That is, these drugs block central dopamine receptors, particularly the D 2 subtype, and thus inhibit dopaminergic neurotransmission in the brain. The postsynaptic receptor blockade in the limbic system is thought to reduce the schizophrenic symptoms.” “ It is believed that although antipsychotic medication block norepinephrine, serotonin, and acetylcholine, their primary action is as central dopamine antagonists. That is, these drugs block central dopamine receptors, particularly the D 2 subtype, and thus inhibit dopaminergic neurotransmission in the brain. The postsynaptic receptor blockade in the limbic system is thought to reduce the schizophrenic symptoms.” Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4 th Ed. Wadsworth: USA. Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4 th Ed. Wadsworth: USA.

NEUROBIOLOGY OF CLOZAPINE All schizophrenic patients do not respond to antipsychotics that have an affinity for DA D 2 receptors. This has lead researchers to believe that there are other Dopamine receptors that may contribute to the cause of schizophrenia. All schizophrenic patients do not respond to antipsychotics that have an affinity for DA D 2 receptors. This has lead researchers to believe that there are other Dopamine receptors that may contribute to the cause of schizophrenia. The DA D 4 subtype has also been implicated in the illness. The DA D 4 subtype has also been implicated in the illness. The DA D 4 is of special interest because of its concentration in the hippocampus and the cerebral cortex. It is through the D 2 and the D 4 receptors that Clozapine exerts its affects. The DA D 4 is of special interest because of its concentration in the hippocampus and the cerebral cortex. It is through the D 2 and the D 4 receptors that Clozapine exerts its affects. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York. Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press: New York.

NEUROBIOLOGY OF CLOZAPINE Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D 4 receptor subtype.

Mechanism of Action The exact mechanism of action unknown, however, it is believed that Clozapine selectively antagonizes dopamine D1 and D4 receptors, serotonin 5-HT2 receptors and others. The exact mechanism of action unknown, however, it is believed that Clozapine selectively antagonizes dopamine D1 and D4 receptors, serotonin 5-HT2 receptors and others. Atypical antipsychotics, like Clozapine, are distinguished by their relatively low affinity for the DA D 2 receptor subtype and its high affinity for the DA D 4 receptor subtype and the 5-HT 2 receptor subtype. Atypical antipsychotics, like Clozapine, are distinguished by their relatively low affinity for the DA D 2 receptor subtype and its high affinity for the DA D 4 receptor subtype and the 5-HT 2 receptor subtype. Clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions Clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions

Mechanism of Action Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of D2 and serotonin 2A receptors, but they can affect many other types of receptors. Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of D2 and serotonin 2A receptors, but they can affect many other types of receptors. Atypical antipsychotics: Atypical antipsychotics: D2 receptor blockade of postsynaptic in the mesolimbic pathway reduce positive symptoms D2 receptor blockade of postsynaptic in the mesolimbic pathway reduce positive symptoms enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway reduce negative symptoms enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway reduce negative symptoms other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

CLOZAPINE Clozapine is considered by many as the only atypical antipsychotic due to its elevated effects over other “atypical” antipsychotics. Clozapine is considered by many as the only atypical antipsychotic due to its elevated effects over other “atypical” antipsychotics. Patients do not experience extrapyramidal symptoms (EPS) Patients do not experience extrapyramidal symptoms (EPS) Used for treatment-resistant patients that have not responded to any other medication. Used for treatment-resistant patients that have not responded to any other medication. Has been shown to have some effectiveness in the treatment of negative symptoms. Has been shown to have some effectiveness in the treatment of negative symptoms. There is a high correlation between patients who take this medication and the development of Agranulocytosis. There is a high correlation between patients who take this medication and the development of Agranulocytosis. Clozapine costs more than typical anti-psychotics, however, the cost is relatively the same for atypical antipsychotics Clozapine costs more than typical anti-psychotics, however, the cost is relatively the same for atypical antipsychotics The effective dose of Clozapine is higher than other atypical antipsychotics. The effective dose of Clozapine is higher than other atypical antipsychotics. Tends to work more effectively in younger patients (20s) than older patients (30s). Tends to work more effectively in younger patients (20s) than older patients (30s). ADVANTAGES DISADVANTAGES

CONCLUSIONS Is there any controversy involved in using this treatment? Is there any controversy involved in using this 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 say that due to the increased risk of attaining Agranulocytosis (which can be fatal is not detected) this drug should be used only if the individual is un responsive to other drugs. However, there has been findings that Clozapine is significantly more affective if administered to the patient at a younger age. The debate is over when this drug should be used. Many say that due to the increased risk of attaining Agranulocytosis (which can be fatal is not detected) this drug should be used only if the individual is un responsive to other drugs. However, there has been findings that Clozapine is significantly more affective if administered to the patient at a younger age. Is this treatment appropriate for every patient? Is this treatment appropriate for every patient? No No Typically Clozapine is used on schizophrenic patients that are treatment-refractory or unresponsive to other medications. Typically Clozapine is used on schizophrenic patients that are treatment-refractory or unresponsive to other medications.

Conclusions What future directions would be necessary to show how the therapeutic intervention impacts on neurobiology? What future directions would be necessary to show how the therapeutic intervention impacts on neurobiology? The cause of schizophrenia is still unknown. To understand how medications for the treatment of schizophrenia work, we must first fully understand the neurobiology of the illness. The cause of schizophrenia is still unknown. To understand how medications for the treatment of schizophrenia work, we must first fully understand the neurobiology of the illness. Therefore, further research should be done on the neurobiology of the illness itself, as well as the secondary neurotransmitters that are altered after Dopamine receptors have been altered by the anti-psychotics medication. Therefore, further research should be done on the neurobiology of the illness itself, as well as the secondary neurotransmitters that are altered after Dopamine receptors have been altered by the anti-psychotics medication. Overall Opinion Overall Opinion My overall opinion of this treatment is in favour of the use of Clozapine for treatment-resistant schizophrenic patients. I believe that other atypicals should be the primary treatment of schizophrenics to reduce negative side effects from the medication. My overall opinion of this treatment is in favour of the use of Clozapine for treatment-resistant schizophrenic patients. I believe that other atypicals should be the primary treatment of schizophrenics to reduce negative side effects from the medication. If such treatment has no effect, doctors should be hasty in switching patients to Clozapine because of the noted efficacy of the drug in younger patients. If such treatment has no effect, doctors should be hasty in switching patients to Clozapine because of the noted efficacy of the drug in younger patients. Although the drug has many advantages, it is not without its disadvantages and patients on Clozapine should be monitored for severe side effects, especially that of Agranulocytosis. Although the drug has many advantages, it is not without its disadvantages and patients on Clozapine should be monitored for severe side effects, especially that of Agranulocytosis.

Works Cited 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. Am J Psychiatry, 158, Belmaker, R. H. (2003). Mechanism of atypicality of antipsychotic drugs. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 27, 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. Am J Psychiatry, 155, Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. 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 treatment of first- and multiple-episode patients with treatment-resistant schizophrenia. International Journal of Neuropsychopharmacology, 6, Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4th Ed. Wadsworth: USA. Shen, Winston. W., (1999). A History of Antipsychotic Drug Development. Comprehensive Psychiatry, 40 (6), THE END