Clozapine is a second-generation antipsychotic drug known as an atypical antipsychotic. It was the first discovered to be effective for treatment-resistant schizophrenia without causing extrapyramidal symptoms. However, it was withdrawn from the market briefly in the 1970s due to cases of agranulocytosis. Three studies summarized found clozapine to be superior to typical antipsychotics like risperidone and haloperidol in improving positive symptoms. While it improved positive symptoms, clozapine did not significantly impact negative symptoms. The mechanism of action is believed to involve antagonizing dopamine D1, D4, and serotonin 5-HT2 receptors.

1. ATYPICAL ANTIPSYCHOTIC
CLOZAPINE
BY: PATRIZIA ORLANDO

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

3. HISTORY OF ANTIPSYCHOTICS
 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.
 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.
 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.

4. 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.
 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), trunk,
and extremities.
 (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.

5. 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.”
 Clozapine was briefly marketed and quickly
withdrawn for two reasons:
 The embarrassment of not having any EPS, and
 Agranulocytosis

6. Side Effects of Clozapine
 Major side effect:
 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:
 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.
 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
 Skin: rashes
 http://www.minddisorders.com/Br-Del/Clozapine.html

7. 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
 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.
 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:
 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.
 Limitations:
 Significant difference in the dosage amount between the groups which
could exert some explanation for the difference in efficacy.

8. 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
 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.
 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.
 Patients receiving Haloperidol worsened in Anhedonia significantly.
 Limitations
 Patients used were not limited solely to those diagnosed with
schizophrenia
 Sample size was small

9. 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:
 Contrasted first and multiple episode male and female patients with
schizophrenia on Clozapine.
 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.
 Results:
 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.
 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 non
responders.
 Limitations:
 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. 263.5mg/d
in this study in comparison to 600mg/d.

10. Dosages and Treatment Length
 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.
 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 discontinuation of all anti-psychotics will cause a
relapse of positive and negative symptoms.

11. 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.
 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.
 Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4th Ed. Wadsworth:
USA.

12. 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.
2. Mesolimbic Pathway
 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.
4. Hypothalamic-Pituitary Pathway
 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.

13. NEUROBIOLOGY OF TYPICAL
ANTIPSYCHOTICS
 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 D2 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 4th Ed.
Wadsworth: USA.

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

15. 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 D4 receptor subtype.

16. 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.
 Atypical antipsychotics, like Clozapine, 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.
 Clozapine may be able to permit more normal
dopaminergic function in the anterior pituitary, the
mesostriatal, mesolimbic and mesocortical regions

17. 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:
 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

18. CLOZAPINE
 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.
 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.
 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.
 Tends to work more effectively
in younger patients (20s) than
older patients (30s).
ADVANTAGES DISADVANTAGES

19. CONCLUSIONS
 Is there any controversy involved in using this
treatment?
 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.
 Is this treatment appropriate for every patient?
 No
 Typically Clozapine is used on schizophrenic patients that are
treatment-refractory or unresponsive to other medications.

20. Conclusions
 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.
 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
 The 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.
 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.

21. 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, 1305-1313.
Belmaker, R. H. (2003). Mechanism of atypicality of antipsychotic drugs. Progress in
Neuro-Psychopharmacology & Biological Psychiatry, 27, 1067-1069.
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, 751-760.
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, 201-206.
Maisto, S. A., Galizio, M., & Connors, G. J., (2004). Drug Use and Abuse 4th Ed.