Treatment Resistant Schizophrenia

1. Action
Indications and Efficacy
Side Effects and Toxicology
Drug-Drug interactions

2. History of Clozapine
 Clozapine was first syntetised in 1958 in Switzerland
and developed in Germany in 1960.
 By 1975 there were 13 cases of agranulocytosis reported
in Finland and 8 of these patients died. Clozapine was
taken off the European market (with the exception of
Finland).
 In the US, Clozapine was approved in 1990 for
treatment resistant schizophrenia.

4. FIN 11 STUDY
 11 years follow up of mortality in patients with
schizophrenia.
 Sought to establish the long term contribution of
antipsychotic drugs to mortality.
 66,881 patients with schizophrenia compared to a total
population of 5.2 million (Finland).
 Mortality data was linked to use of antipsychotic
prescriptions using public registers.
RESULTS
 Atypical antipsychotics were associated to lower mortality
as compared to typical antipsychotics or to no medications
at all.
 Clozapine had the lowest mortality rate.

5. What Have We Learned from Clozapine
Which of the following dopamine receptor subtypes is
of great psychopharmacological interest because of
clozapine’s high affinity for this receptor?
1. D1
2. D2
3. D3
4. D4
5. D5

6. Where in the World are D4
receptors?

7. Clozapine
X
M1 M3
H1
5HT2A
1
2
D1
D2
D3
D4

8. Conventional antipsychotic: Clozapine occupies only 20-67% of D2
90% of striatal D2 receptor receptors
occupied

9. Clozaril thought us about partial
agonists

10. A partial agonist can have a net effect
of an agonist or an antagonist
 When the full agonist is absent, the partial agonist
increases the frequency of the channel opening as
compared to a resting state (acts as a net agonist).
 When the full agonist is present, the partial agonist
decreases the frequency of the channel opening as
compared to a resting state(acts as a net antagonist).

11. Action of an agonist

12. Action of an antagonist – the
channel remains in its resting state

13. Antagonist can displace an agonist and
return the channel to its resting state

14. Inverse agonists render the
channel inactive

15. In the presence of an inverse agonist,
an antagonist returns the channel to its
resting state

16. Clozapine Indications and Efficacy
 Acute Schizophrenia and Schizoaffective disorder
 Treatment refractory schizophrenia
 Hostile and Aggressive Behavior in Schizophrenia
 Schizophrenia patients with high risk for suicide
 Schizophrenia with Comorbid Substance Abuse
 Maintenance Therapy in Schizophrenia

17. Prior to Initiation of
ClozapineTreatment
 Need a baseline WBC count (≥3500/mm3)
 Need an Absolute Neutrophil Count (ANC) (≥
2000/mm3)
 Clozaril Registry ensures monitoring of WBC and
ANC.

18. Initiation of Treatment
 Begin with one-half of a 25-mg tablet (12.5 mg) once or
twice daily and then continue with daily dosage
increments of 25-50 mg/day, if well tolerated, to
achieve a target dose of 300-450 mg/day by the end of
2 weeks.

19. Time frame of an adequate
clozapine trial
 Carpenter vs. Meltzer : 3 months vs. 1 year
According to Meltzer – late responders further
benefit up to 1 year.
 In reality, what constitutes a reasonable trial?
 6-12 weeks at adequate doses

20. What is an adequate dose of
clozapine?
 Good evidence for greater efficacy if Clozapine
blood level is >350 ng/ml
 350 – 450 ng/ml appears optimal. In case of poor/
no response, can titrate to a plasma level >450
ng/ml.
 Dose range 175 – 825 mg/day to achieve these levels
across patients.

21. Treatment Resistant Schizophrenia
 In a pivotal study of Clozaril Kane J, Honigfeld G, Singer J
et al. Clozapine for the treatment-resistant
schizophrenic. A double blind comparison with
chlorpromazine. Arch. Gen Psychiatry. 1988;45(9):789-
7896.
 At lest 3 periods of treatment in the preceding 5 years
with neuroleptic agents from at least 2 different
chemical classes at dosage equivalent to 1000 mg/day
of chlorpromazine for 6 weeks, each without
significant symptomatic relief, and no period of good
functioning within the preceding 5 years.

22. Why is schizophrenia treatment
resistant?
 Neurodegeneration occurs during psychosis.
 Excitotoxicity
 Intracellular Calcium homeostasis

23. Intracellular Calcium Homeostasis
 Calcium is a very common signaling element and plays a critical
role in the CNS by regulating the activity of diverse enzymes,
facilitating neurotransmitter release and long term potentiation
(memory).
 Excessively high levels of Calcium in the neuron cause damage
by activating the cell death cascade (apoptosis).
 For this reason the neurons, developed diverse homeostatic
mechanisms to regulate intracellular Calcium level very
precisely.
 Thus extracellular Calcium level is approximately 2 mM, while
the resting intracellular Calcium level is in the range of 100nM
(20,000 times less).

24. Intracellular Calcium Homeostasis
 In order to keep tight control of the intracellular Calcium, the neuron
developed Calcium pumps(to eliminate it), and Calcium proteins to carantine
it . Thus it is estimated that Calcium ion can only diffuse 0.5 micrometers and
is free for only 50 microseconds before encountering a Calcium binding protein
to sequestrate it.

25. Why is Psychosis “bad for your
brain”?
 During normal excitation, entry of small amounts of Calcium in the
neuron is beneficial – it forms the basis of long term potentiation
(memory).
BUT
 Studies have shown that during psychotic episodes excessive amounts
of Calcium enter the neurons, leading to the destruction of the
organelles and the activation of cell death cascade (apoptosis). This
process is called EXCITOTOXICITY

28. Other Indications- Show me the
Evidence
 Hostile and Aggressive Behavior in Schizophrenia
 Schizophrenia patients with high risk for suicide
 Schizophrenia with Comorbid Substance Abuse
 Maintenance Therapy in Schizophrenia

29. Hostile and Aggressive Behavior in
Schizophrenia

30. Clozapine is of particular benefit to the patients
with treatment of refractory schizophrenia who
demonstrate hostile and aggressive behaviors
 A number of studies suggest that Clozapine may
decrease hostility and aggression, compared with
other agents.
 Citrome et al. (2001): in a study of 157 inpatients,
Clozapine resulted in greater reduction in hostility
item from the PANSS than both typical and atypical
antipsychotics.
 Chengappa et al(2003) found significant reduction in
the rates of seclusion and restraints in schizophrenia
patients who received Clozapine during the first 3
years after its introduction on the market.

31. Schizophrenia Patients with High
Risk for Suicide

32. Clozapine decreases suicidality
 Large epidemiological studies have found that
mortality from suicide is reduced among individuals
taking Clozapine (Reid et all 1988; Walker et all
1997; Meltzer and Okayali 1995).
 The most convincing study was a comparison of
Clozapine and Olanzapine in 980 patients with
schizophrenia who were considered at risk for suicide
(Meltzer 2002). In this study Clozapine was more
effective in reducing the risk of suicide.

33. Schizophrenia with Comorbid
Substance Abuse
 The effectiveness of Clozapine in patients with
comorbid substance abuse has not been
demonstrated in randomized clinical trials, there is
some supporting evidence from naturalistic studies.
 Greene (2003) found that patients treated with
Clozapine were more likely than those treated with
Risperidone to abstain from alcohol and cannabis use.
 These findings were supported by other prospective
studies (Brunette et al. 2006 and Drake et al 2000).

34. Maintenance Therapy in
Schizophrenia
 Clozapine has largely been confined to patients with treatment resistant
schizophrenia. As a result it was not studied in the traditional relapse
prevention trials in which patients who are stable are randomly assigned to
either Clozapine or a comparator drug.
 Nevertheless, there are substantial data supporting the long term effectiveness
of Clozapine.
 Breier et al.(2000) evaluated the outcomes of 30 patients with schizophrenia
who were treated with Clozapine for 1 year. Patients taking Clozapine
experienced fewer relapses and rehospitalizations than they did in the year
prior to being on Clozapine.
 A study in the State hospitals in Connecticut, done by Essock et al. in 2000,
compared patients who were on Clozapine to the patients maintained on other
antipsychotics. Although Clozapine did not result in a greater likelihood of
hospital discharge, patients who were treated with Clozapine had higher
likelihood of remaining in the community after discharge.

35. Side Effects and Toxicology
Why not first line treatment?
 Even though it is very effective, Clozapine is not
considered a first-line agent because it can lead to the
potentially life-threatening side effect agranulocytosis.
 Weight increase and the concomitant risk of
developing metabolic complications are greatest with
clozapine

36. Hematological Effects
 The side effects of Clozapine make it one of the most challenging
medications to prescribe.
 The main factor that limits its use is the potential serious side
effect of agranulocytosis (defined as a drop in absolute neutrphil
count to levels below 500/cubic mm.
 In a review of morbidity and mortality of Clozapine treated
patients done by Honigfeld et al. in 1998, over a 5 year period,
99,502 patients were registered through the Clozaril National
Registry. Of these 2,931 developed leukopenia (WBC
3,500/cubicmm), and 382 patients developed agranulocytosis
(ANC below 500/cubicmm). 12 cases of agranulocytosis were
fatal. This study shows lower percentage of agranulocytosis than
initially thought, leading to change in FDA guidelines in 2006.

37. Agranulocytosis
 The onset of agranulocytosis occurs most often during the
first 6 months of treatment and is usually marked by a
gradual fall in WBC count, often over several weeks.
 Thus patients must be monitored with weekly blood cell
counts for the first 6 months of treatment and every 2
weeks thereafter.
 Dr. Schatzberg and his group believe in the allergic etiology
of thrombocytopenia. This theory was not validated yet by
other studies, but frequently agranulocytosis is preceded
by eosinophilia . Also when a patient who once had
agranulocytosis is re-challenged with Clozapine, the drop
in WBC occurs sooner and is more severe, suggesting an
allergic etiology.

38. Cardiovascular Adverse Effects
 Tachycardia – caused by anticholinergic activity.
 Orthostatic hypotension – alpha adrenergic
blockade.
 Myocarditis
 Cardiomyopathy

39. Cardiac Effects
 In January 2002 Novartis reported that there had been 213 cases of
myocarditis, 85% of which occurred at recommended dosages of
Clozapine within the first 2 months of treatment. The presence of
eosinophilia in many of the reported cases indicates that an
immunoglobulin E mediated hypersensitivity reaction may be
involved.
 In 2002 Novartis also reported 178 cases of Clozapine associated
cardiomyopathy, 80% of which occurred in patients younger than 50.
Almost 20% of these incidents resulted in death. The detection of
cardiac toxicity is particularly challenging because its manifestations
(tachycardia, fatigue and orthostatic hypotension) are frequently
observed in Clozapine treated patients.
 Merril and Goff in 2005 conducted a thorough review of the literature
examining reports from 1970-2004 of cardiac side effects in patients on
Clozapine. They concluded that Clozapine is associated with a low risk
(0.015%-0.188%) of potentially fatal myocarditis or cardiomyopathy.

40. Weight Gain

41. Weight Gain
 In patients observed in various clinical trials, the average weight
gain in 6 months period with Clozapine treatment was 6.9 Kg.
 Allison et al. (1999) performed a meta-analysis of weight gain
data in in short-term trials of medications. The average weight
gain observed with Clozapine was 4.45 Kg, which exceeded the
weight gain observed with all the other medications in the study,
including conventional agent Thioridazine(3.19 Kg), a
medication known for its weight gain liability.
 Henderson (2001) observed patients in a Clozapine clinic for 5
years and noted weight gain occurring for up to 46 months in
some patients.

42. Diabetes
 Numerous case reports have linked Clozapine with new onset diabetes.
 Henderson(2001) naturalistic study of 81 patients observed over a 5
year period, 36.6% of the patients developed diabetes. (The prevalence
of diabetes in the US is estimated to be 7%, with another 7% of cases
undiagnosed).
 Koller et al.( 2001)published the largest series of case reports
submitted voluntarily to the FDA Med Watch Program. The report
revealed that there were 2,424 new onset cases, 54 of which were cases
of diabetic exacerbation and 80 of which were cases of diabetic
ketoacidosis.
 Newcomer(2006) concluded that antipsychotic medication-
associated adiposity is the main culprit in the development of diabetes.
 Sasaki et al (2006) showed that the etiology of diabetes may be
independent of adiposity, instead reflecting the direct blockade of
muscarinic(M3) receptors on the pancreatic beta cells.

43. Blocking M3 Cholinergic Receptors: Reduces Insulin
Release
ACh
presynaptic
parasympathetic M3
fibers
insulin
postsynaptic
cholinergic beta cells
fibers
SDA
insulin

44. Insulin Resistance / Elevated Triglycerides and
Antipsychotics: Caused by Tissue Actions at an
Unknown Receptor?
atypical
insulin
adipose
liver
skeletal
muscle
receptor x

45. Dyslipidemias
 Gaulin et al.(1999) compared 117 patients taking
Clozapine with 45 taking Haloperidol. The study
found significant increase in triglyceride levels for
both men and women taking Clozapine – a mean
increase from 184.6 mg/dl to 273.4 mg/dl for men and
164.9 mg/dl to 223.3 mg/dl for women.
 More recently Mc Evoy et al.(2006) looked at the
patients who received Clozapine in phase II of CATIE
study and demonstrated greater elevations in both
triglycerides and cholesterol as compared to the
patients on Risperidone, Olanzapine or Quetiapine.

46. Analyze This
 Could triglyceride elevations account for the beneficial psychiatric effect
of these medications through stabilization of neuronal membranes?
 Kingsburry et al.(2001) showed correlations between elevations in
triglyceride levels and changes in mood.
 Diebold et al( 1998) showed that increase in trigliceride levels was
associated with decreased hostility.
 Spivak et al (1998) observed that patients taking Clozapine who developed
increase in triglycerides also demonstrated decreases in aggression and suicidal
behavior in comparison with people taking typical antipsychotics.
 Muldoon et al (1990) a cardiologist reviewed numerous randomized clinical
trials that focused on reducing lipid levels for primary prevention of coronary
artery disease. They concluded that the risk of death due to accidents, suicide,
or violence was significantly higher in patients with reduced lipid levels.

47. Thought Provoking:
 To examine whether the medical consequences of obesity
may offset the life saving benefits gained from Clozapine’s
potentially decreased suicide rate, Fontaine et al(2001),
using mathematical modeling, estimated that 492 suicide
deaths per 100,000 schizophrenia patients would be
prevented over 10 years with the use of Clozapine. This was
compared with an estimated 416 additional deaths due to
antipsychotic induced weight gain. Even though
controversial, this mathematical model suggests that
the lives saved by Clozapine may essentially be offset
by the death associated with weight gain. These
findings were confirmed by the FIN 11 study (published in 2010).
 Nature is subtle, but not malicious (Einstein)

49. Seizures
 A well known risk of Clozapine treatment is the risk for seizures,
which are thought to occur in 5%-10% of patients treated with
this medication.
 Clozapine-associated seizures occur most often at doses greater
than 600 mg /day.
 The relationship between Clozapine plasma levels and and
seizures is inconsistent throughout the literature
 It is recommended obtaining a baseline EEG when initiating
Clozapine treatment in patients who have a history of possible
head injury, loss of consciousness, or other risk factors for
seizures.

50. Constipation
 A truly problematic consequence of clozapine’s
anticholinergic activity is its propensity to cause significant
constipation.
 In institutional settings where patients have limited access
to exercise and where monitoring of fluid intake is not
performed, constipation from Clozapine can be serious or
even fatal.
 The favored medical treatment is prophylaxis with sorbitol
( 3.3 % in plastic irrigation containers).
 High fiber diets, exercise and hydration are also very
helpful.

51. Drug-Drug Interaction
 Clozapine is predominantly metabolized by cytochrome
P450 1A2, although CYP 2D6 and CYP 3A3 also contribute
to its metabolism.
 Smoking which induces CYP 1A2, lowers clozapine plasma
level.
 Fluvoxamine(Luvox) is a potent inhibitor of CYP 1A2 for
this reason it increases plasma levels of Clozapine.
 Inhibitors of CYP 2D6, such as Paroxetine and Fluoxetine
can elevate Clozapine levels.

52. Thank you
ADONIS SFERA MD