ATYPICAL ANTIPSYCHOTIC

CLOZAPINE
BY: PATRIZIA ORLANDO

CLOZAPINE

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

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

which gives the appearance of Parkinsonism.) .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. and extremities. (30-50% of patients experience these side effects while on typical antipsychotic medication. trunk.    Dyskinesia: disordered movements Akinesia: slowness of movement and underactivity Tardive Dyskinesia: repetative unvoluntary movement of the mouth and tongue ( often in the form of a lip smacking).   Negative Symptoms: typical antipsychotics seemed to have little to no improvement in negative symptoms.

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OF THE ATYPICAL ANTIPSYCHOTIC   “German psychiatrists working with G.” Clozapine was briefly marketed and quickly withdrawn for two reasons:   The embarrassment of not having any EPS.

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

M. Results:   Magnitude of the response (determined by BPRS and CGI scores) was significantly greater in the Clozapine group. and 201 patients completed the study. consent withdrawal.A Double-Blind Comparative Study of Clozapine and Risperidone in the Management of Severe Chronic Schizophrenia By: Azorin. . Reasons for leaving the study included adverse event.   STUDY 1   Type of study: Double-blind comparative study Population: Male and female patients aged 18-65 years who met the DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response. and death (unrelated to therapy). J.  Limitations:  Significant difference in the dosage amount between the groups which could exert some explanation for the difference in efficacy. treatment failure. protocol violation. et al. Patients:Total of 273 patients were randomly assigned to one of the two groups. Clozapine exhibited clear therapeutic superiority over Risperidone for the majority of the efficacy measures.

Clozapine was superior to Haloperidol in treating positive symptoms. relapse. and low RBC count. and withdrawal of consent. Patients receiving Haloperidol worsened in Anhedonia significantly. Results:    Limitations   For patients that completed the 10 week double blind study. seizures. R. Patients: 64 of the 75 patients completed the study. STUDY 2     Type of study: 10 week Double-blind. et al. Patients used were not limited solely to those diagnosed with schizophrenia Sample size was small .Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome By: Buchanan. W. 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. however. there was no long term effect of Clozapine on primary or secondary negative symptoms. Reasons for drop out was for noncompliance.

noncompliance.9.The safety of clozapine in the treatment of first. No significant difference in side effects between the groups. et al. compared to 31. Large number of unexpected drop-outs related to geographical distribution of patients. 263.  STUDY 3 Population:   Patients:  Contrasted first and multiple episode male and female patients with schizophrenia on Clozapine. Dosages of Clozapine are seen to be lower than in the average study. Negative association between age and response rate.1 +/. side-effects.  Results:     Limitations:   .5mg/d in this study in comparison to 600mg/d. and logistic reasons. Response and side effects to Clozapine treatment do not seem to be determined by the chronicity of the disorder.and multiple-episode patients with treatment-resistant schizophrenia By: Hofer. The mean age of responders was 26. Only 52 of the 95 patients completed the study.9 years of non responders. 39 first-episode patients and 56 multiple-episode patients who were resistant to other treatments. A.9 years.2 +/. Reasons for premature termination was admission to a secure unit.

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

M. (2004). Galizio.. and muscle tone.. & Connors.  . The Hypothalamus: the effects on this areas generally serve to modulate metabolism. J. Maisto. G.. alertness. The Limbic System: the effects on this area generally serves to moderate or blunt emotional arousal. Wadsworth: USA. S.BRAIN AREAS INVOLVED IN ANTIPSYCHOTIC TREATMENT  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. A. Drug Use and Abuse 4th Ed.

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

particularly the D2 subtype. Galizio. S. their primary action is as central dopamine antagonists.. serotonin. G.”  Maisto. Drug Use and Abuse 4th Ed. . M. and acetylcholine. The postsynaptic receptor blockade in the limbic system is thought to reduce the schizophrenic symptoms. A. (2004). and thus inhibit dopaminergic neurotransmission in the brain. & Connors. That is. Wadsworth: USA.. these drugs block central dopamine receptors.NEUROBIOLOGY OF TYPICAL ANTIPSYCHOTICS  The Dopamine Hypothesis  “ It is believed that although antipsychotic medication block norepinephrine. J..

. This has lead researchers to believe that there are other Dopamine receptors that may contribute to the cause of schizophrenia.  . It is through the D2 and the D4 receptors that Clozapine exerts its affects. Oxford University Press: New York. W. R.NEUROBIOLOGY OF CLOZAPINE    All schizophrenic patients do not respond to antipsychotics that have an affinity for DA D2 receptors. The DA D4 is of special interest because of its concentration in the hippocampus and the cerebral cortex. In Search of Madness: Schizophrenia and Neuroscience. (2001). The DA D4 subtype has also been implicated in the illness. Heinrichs.

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

serotonin 5-HT2 receptors and others. like Clozapine.Mechanism of Action    The exact mechanism of action unknown. are distinguished by their relatively low affinity for the DA D2 receptor subtype and its high affinity for the DA D4 receptor subtype and the 5-HT2 receptor subtype. mesolimbic and mesocortical regions . the mesostriatal. Clozapine may be able to permit more normal dopaminergic function in the anterior pituitary. Atypical antipsychotics. however. it is believed that Clozapine selectively antagonizes dopamine D1 and D4 receptors.

but they can affect many other types of receptors.Mechanism of Action   Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of D2 and serotonin 2A receptors. Atypical antipsychotics:  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  other receptor-binding properties may contribute to efficacy in treating cognitive symptoms. aggressive symptoms and depression in schizophrenia .

   There is a high correlation between patients who take this medication and the development of Agranulocytosis. Tends to work more effectively in younger patients (20s) than older patients (30s). the cost is relatively the same for atypical antipsychotics The effective dose of Clozapine is higher than other atypical antipsychotics.CLOZAPINE ADVANTAGES  DISADVANTAGES     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) Used for treatment-resistant patients that have not responded to any other medication. . however. Has been shown to have some effectiveness in the treatment of negative symptoms. Clozapine costs more than typical anti-psychotics.

there has been findings that Clozapine is significantly more affective if administered to the patient at a younger age. No Typically Clozapine is used on schizophrenic patients that are treatment-refractory or unresponsive to other medications.CONCLUSIONS  Is there any controversy involved in using this treatment?    Is this treatment appropriate for every patient?   There is some controversy surrounding this drug. 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. The debate is over when this drug should be used. However. .

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

A Double-Blind Comparitive Study of Clozapine and Risperidone in the Management of Severe Chronic Schizophrenia. & Carpenter. The safety of clozapine in the treatment of first.. Kirkpatrick. In Search of Madness: Schizophrenia and Neuroscience. & Bourdeix. W. Hofer. M. W. J. R. 751-760. Hummer.. Kemmler. Buchanan. (2001). H. . Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome. I.... A. International Journal of Neuropsychopharmacology. J. Heinrichs. G. Kurzthaler. P. M. M.. J. R.. Ball. (2004). R. Maisto. G.Works Cited Azorin. 158. Breier. 6. T. A. Pere. Remington.. I. Belmaker.. (2003). Kurz.. 1067-1069. J. W. .. R. Progress in Neuro-Psychopharmacology & Biological Psychiatry. & Connors.. Galizio. (1998). G. & Fleischhacker.. iguere. Am J Psychiatry. 201-206. Vanelle.. Drug Use and Abuse 4th Ed. A.. Am J Psychiatry. (2001).and multiple-episode patients with treatment-resistant schizophrenia. M.. Spiegel. 27.. W. Oxford University Press: New York. S. (2003). Mechanism of atypicality of antipsychotic drugs. 155. W.. B. 1305-1313.