This document discusses the treatment of schizophrenia and selection of antipsychotic medications. It provides information on: - The core symptoms of schizophrenia and their association with brain circuits and dopamine pathways. - The evolution of antipsychotic medications from first-generation to second-generation drugs with multiple receptor mechanisms of action. - Principles of selecting antipsychotics based on individual patient factors like efficacy, tolerability, adherence, and cost. - Details on how different antipsychotics bind to dopamine and other receptors and the implications for symptoms, side effects, and dosing schedules.

2. Prof. Hani Hamed Dessoki, M.D.Psychiatry
Prof. Psychiatry
Chairman of Psychiatry Department
Beni Suef University
Supervisor of Psychiatry Department
El-Fayoum University
APA member

3. Schizophrenia Core Symptoms
Psychotic Deficit Cognitive
Positive
Symptoms
Mesolimbic pathway
Negative
Symptoms
DLPC &VMPFC
Cognitive
Dysfunction
DLPFC
Affective
VMPFC

4. Mesocortical
/prefrontal
cortex
Symptoms May Match To Malfunctioning
Brain Circuits
)Conlry.R, 2007(
Positive
symptoms
Mesolimbic
Negative
symptoms
Nucleus
accumbens
reward circuits
Cognitive
symptoms
Dorsolateral
prefrontal cortex
Dopamine
Aggressive
symptoms
AmygdalaOrbitofrontal
cortex
Affective
symptoms
Ventromedial
Prefrontal
cortex

5. Then and Now: The Evolution of
Antipsychotics
Preskorn SH. Psychiatr Pract. 2001 ;7(3):209-13.
1950s
Multiple mechanisms
of action
(eg. chlorpromazine)
1990s
Multiple mechanisms
of action
(„atypical” antipsychotics)
1970s
Single mechanism
of action
(eg. haloperidol)

6. AsenapineAsenapine
BifeprunoxBifeprunox
PaliperidonePaliperidone
IloperidoneIloperidone
’’30s ’40s ’50s ’60s30s ’40s ’50s ’60s ’70s ’80s ’90s & ’00’70s ’80s ’90s & ’00 ’06-’08’06-’08
ElectroconvulsiveElectroconvulsive
therapytherapy
ChlorpromazineChlorpromazine
HaloperidolHaloperidol
FluphenazineFluphenazine
ThioridazineThioridazine
LoxapineLoxapine
PerphenazinePerphenazine
First GenerationFirst Generation
AntipsychoticsAntipsychotics
(FGAs)(FGAs)
Second GenerationSecond Generation
AntipsychoticsAntipsychotics
(SGAs)(SGAs)
RisperidoneRisperidone
OlanzapineOlanzapine
QuetiapineQuetiapine
ZiprasidoneZiprasidone
AripiprazoleAripiprazole
Developments in the Treatment
of Schizophrenia
ClozapineClozapine

11. The Concept of Treatment Effectiveness
Efficacy Tolerability
Adherence/
Persistence
Treatment
Effectiveness
Lehman AF, et al. Am J Psychiatry 2004;161(suppl 2):1-56.
Swartz MS, et al. Schizophr Bull 2003;29(1):33-43.

12. Terminology of “Treatment Response”
Term Symptom
reduction
Adverse
effect &
Tolerability
Cost
a)-Efficacy: + - -
b)-Effectiveness : + + -
c)-Efficiency : + - +

13. Introduction
Knowing how antipsychotic drugs workhow antipsychotic drugs work at specific
receptor sites helps the clinician select the drug of
choice for an individual patient.
Older and newer antipsychotics show, in general,
approximately the same efficacyapproximately the same efficacy in countering
psychotic symptoms.

14. D1
D4.2
D2
5-HT2A
5-HT2C
5-HT1A
5-HT6
α1
α2
Musc
H1
Olanzapine Clozapine
Risperidone
Quetiapine
Ziprasidone Haloperidol
The Search for a Broad Spectrum Receptor-Binding Profile
Distinct from Conventional D2 Predominant Antagonists
Schotte A, et al. Psychopharmacology (Berl). 1996;124(1-2):57-73.
Lawler, C, et al. Neuropsychopharmacology. 1999;20(6):612
Aripiprazole

15. Receptor Systems Affected by Atypical
Antipsychotics
risperidone D2, 5-HT2A
, 5-HT7
, α1
, α2
sertindole D2, 5-HT2A
, 5-HT2C
, 5-HT6
, 5-HT7
, D3, α1
ziprasidone D2, 5-HT2A
, 5-HT1A
, 5-HT1D
, 5-HT2C
, 5-
HT7
, D3, α1
, NRI, SRI
loxapine D2, 5-HT2A
, 5-HT6
, 5-HT7
, D1, D4, α1
, M1
,
H1
, NRI
zotepine D2, 5-HT2A
, 5-HT2C
, 5-HT6
, 5-HT7
, D1, D3,
D4, α1
, H1
, NRI
clozapine D2, 5-HT2A
, 5-HT1A
, 5-HT2C
, 5-HT3
, 5-HT6
,
5-HT7
, D1, D3, D4, α1
, α2
, M1
, H1
olanzapine D2, 5-HT2A
, 5-HT2C
, 5-HT3
, 5-HT6
, D1, D3,
D4, D5, α1
, M1-5
, H1

16. Principles of Antipsychotic Access,
Efficient Utilization and Prescribing
1. Treatment with antipsychotic medications, like any
other treatment, should be individualizedindividualized in order to
optimally promote recovery.
2. Treatment with antipsychotic medication should be
as effectiveeffective, safesafe and well-toleratedwell-tolerated as possible.
3. Treatment with antipsychotic medication should
consider personal preferencepersonal preference and vulnerabilities.vulnerabilities.

17. Principles cont’d
4. Treatment with antipsychotic medication should
provide value in terms of improved quality ofimproved quality of
lifelife to the consumer.
5. Treatment choices should be informed by the
best current evidencebest current evidence and must evolve in
response to new information.
6.6. Cost considerationsCost considerations should guide
antipsychotic medication selection if the
preceding principles are met.

18. Clinical Decision Making:
Weighing Risks and Benefits
Discontinue
Manage adverse
events vs.
Discontinue?
Intolerable
Adverse Events
Discontinue vs.
Augment?
Continue current
therapy
Tolerable
Adverse Events
Poor ResponseGood Response
Discontinue
Manage adverse
events vs.
Discontinue?
Intolerable
Adverse Events
Discontinue vs.
Augment?
Continue current
therapy
Tolerable
Adverse Events
Poor ResponseGood Response

19. Antagonist
Partial
AgonistAgonist Antagonist
Inverse
Partial
Agonist
Partial
Agonist
Inverse
AgonistAgonist
Binding to Receptors
Agonists & Antagonists bind competitively - beware misunderstandings
from binding data without further functional analysis
Endogenous agonists often bind weakly (enthalpy driven)
Successful antagonists often bind tightly (entropy driven)

20. What is ligand efficacy?
• Agonist: Ligand that binds
to a receptor and
produces a response
• Partial agonist: Produces
an effect less than the
maximum
• Antagonist: Ligand that
binds but does not cause
activation
• Inverse Agonist: Binds
and produces the opposite
response to the agonist
Full Agonist
Antagonist
Partial Agonist
Inverse Agonist
log [Ligand] (M)
ReceptorActivity

21. Typical vs. atypical
psychlotron.org.uk

22. The affinity, or more precisely, the dissociationdissociation
constant (K)constant (K) of dopamine for the high-affinity
state of the D2 receptor is between 1.7 and 1.8
nM (nanomoles of dopamine per liter of water).
The traditional antipsychoticstraditional antipsychotics generally have
dissociation constants lower than 1.75 nMlower than 1.75 nM, which
means that they are more tightly bound to D2
compared with dopamine.
Difference Between Low and High
States cont’d

23. Does 65% Occupancy Need to Be
Maintained Full Time? (cont.)
The new so-called atypicalatypical antipsychotics, such as
clozapine, quetiapine, amisulpride, and remoxipride
merely "block and run”"block and run” (but at different speeds).
For instance, the atypical, sertindolesertindole, and olanzapineolanzapine, dissociates
from the D2 receptor moremore slowlyslowly than clozapine or quetiapine, but
more quickly than haloperidol or chlorpromazine.

24. Relative Binding of Antipsychotics
To D2 Receptors
Quetiapine
Clozapine
Olanzapine
Sertindole
Risperidone
Ziprasidone
Chlorpromazine
Haloperidol
Fluphenazine
“Loose”
“Intermediate”
Dopamine K (1.5nM)
“Tight”
KatD2(nM)
100
10
1
0.1

25. Relevant Occupancy
The blockade needed to alleviate psychotic
symptoms is approximately two thirds or 65%two thirds or 65% of
the population of D2 receptors (e.g. basal ganglia
or striatum).
When fewer than 60%fewer than 60% of receptors are occupied
(ie, when subthreshold doses are prescribed or
when medication is not taken as prescribed), thethe
symptoms of psychosis return.symptoms of psychosis return.

26. Motor Side Effects
The emergence of motor side effects with using of
typical antipsychoticstypical antipsychotics depends on the exact
percentage of occupied D2 receptors (80%80%
occupancy of D2).
However, patients on the new atypical compound,
Sertindole andSertindole and aripiprazolearipiprazole, may not exhibit
parkinsonism even with 90% occupation of D2
receptors.

27. In general, for first-generation antipsychotics, the
effective dose range before motor side effects set is
relatively narrowrelatively narrow.
So raising the dose of haloperidol, for instance,
from 2 mg per day to 4 mg per day2 mg per day to 4 mg per day may
overshootovershoot the 80%80% occupancy place a patient over
the threshold for the development of EPS.
Motor Side Effects (Cont.)

28. Brain imaging studies indicate that the traditional
antipsychotics stay attached to dopamine D2
receptors for at least 1 or 2 days following an oralat least 1 or 2 days following an oral
dosedose (daily administration is unnecessary & problematic).
Receptor proliferation not only requires
progressively higher doses in order to maintain
efficacy but, in addition, is probably responsible for theis probably responsible for the
development of tardive dyskinesia.development of tardive dyskinesia.
Does 65% Occupancy Need to Be Maintained
Full Time? (cont.)

29. Clozapine and quetiapine should be taken daily.
Sertindole, olanzapine and risperidone should
probably be taken every second day.
Haloperidol and chlorpromazine every third day.
Thus maintaining intermittent 65% occupancy.
Does 65% Occupancy Need to Be Maintained
Full Time? cont’d

30. Why Psychotic Symptoms Wane With Age?
Under untreated conditions,Under untreated conditions, the number of
receptors diminishes as the person ages.
This explains, perhaps, the age-related reduction ofage-related reduction of speed of
arousal, of peaks of pleasure, of frequency of impulsive behavior --
all experiences mediated by dopamine.mediated by dopamine.

31. Why Higher Doses Are Required Over
Time
In patients treated over long periods of time with
antidopaminergic drugs, receptor proteins adaptadapt
to blockade by creating more D2creating more D2 receptors
(receptor proliferation).
So that, in chronically treated schizophrenia
patients, receptor numbers risereceptor numbers rise and
maintenance doses increase at the same time.

32. Treating patients who are undergoing stress.
Treating first episode
Treating non adherent patients
Treating patients with a family history of
osteoporosis
Treating cardiac patients or those with a
family history of cardiac disease.
Choosing antipsychotic & why?

33. Treating patients with a family history of
diabetes
Avoiding obesity
Treating patients with sexual dysfunction
Treating treatment refractory patients
Treating women
Treating child and adolescents
Choosing antipsychotic & why?
(cont.)

34. Treating Patients Who Are Undergoing
Stress
Those whose stress levels are high (ie, increased
levels of endogenous dopamine are being
released) may find that the attachment period to the
receptor of these 2 drugs (quetiapine and clozapine)
is too short for symptom control.is too short for symptom control.
The therapeutic concentration of the antipsychotic in
the presence of abundant dopamine will need to be
proportionally higherhigher than that needed in periods of
calm.

35. Treating First Episodes
Young patients with a first episode of psychosis
respond equally well to first- and second-first- and second-
generation drugsgeneration drugs, but tolerability of the drug regime
is especially important in this population.

36. Treating Non Adherent Patients
Patients known to be non adherentnon adherent to regular
medication will do better on those drugs that are
relatively tightly bound to the D2 receptortightly bound to the D2 receptor (where
relapse due to a brief period of noncompliance is a lesser risk).
Monthly depot medicationMonthly depot medication is stillstill the treatment of
choice for the extremely non adherent.

37. Problems Hinder AchievingProblems Hinder Achieving
Non adherence to treatment
Medication compliance is poor in
patients with Schizophrenia
Medication compliance is poor in
patients with Schizophrenia
Coldham EL, et al. Acta Psychiatr Scand 2002;106:286–90Coldham EL, et al. Acta Psychiatr Scand 2002;106:286–90
39%
Non- compliant
39%
Non- compliant
41% Compliant41% Compliant41% Compliant41% Compliant
20%
Partially compliant
20%
Partially compliant

38. NICE guidelines;
For people with newly diagnosed (first episode)
schizophrenia,
National Clinical Practice Guideline Number 82. National Institute
for Health and Clinical Excellence 2009.

39. Treating Patients With a Family History of
Osteoporosis
Patients with a family history of osteoporosis are best
not treated with drugs that raise prolactin levels.not treated with drugs that raise prolactin levels.
This is especially true for womenespecially true for women because they
develop osteoporosis at a younger age than men.
Normal serum prolactin levels are considered to be
between 5 and 25 micrograms/L5 and 25 micrograms/L.

40. Potential consequences of prolactinPotential consequences of prolactin
elevationelevation
Amenorrhoea
Loss of libido
Impotence
Erectile
dysfunction
Osteoporosis
 bone density
Prolactin
Elevation
Gynaecomastia
Galactorrhoea

41. Treating Cardiac Patients or Those With a Family
History of Cardiac Disease
The QTc interval (approximate range is 350-440 milliseconds350-440 milliseconds [ms])
represents the duration of ventricular depolarization and repolarization.duration of ventricular depolarization and repolarization.
It is generally accepted that QTc intervals exceeding 500 msexceeding 500 ms are associated
with an increased riskan increased risk of a lethal paroxysmal ventricular tachycardiaa lethal paroxysmal ventricular tachycardia
(torsades de pointes).

42. Drug effects on QTc interval
QTc prolongation occurs with:
Thioridazine > 35 msec
Pimozide > 30 msec
Sertindole > 20 msec
Ziprasidone > 17 msec
Haloperidol > 11 msec
Risperidone > 3 msec
Olanzapine > 2 msec

43. Treating Patients With a Family History of
Diabetes
The base rate of diabetes in the schizophrenia
population is thought to be between 5.6% and 6.7%.
It is substantially higherhigher than in the general
population, probably because of relative inactivity
and the high prevalence of smoking, poor dietsmoking, poor diet and
obesityobesity.

44. Treating Patients With a Family History
of Diabetes cont’d
The novel antipsychotics have more propensity for
inducing insulin resistance: clozapine, olanzapine,
and quetiapine cause the highest rates of diabetes;
sertindolesertindole, risperidonerisperidone and ziprasidoneziprasidone are
associated with lower rates.
Patients with a family history of diabetes and with
other concurrent risk factors should be treated with
sertindolesertindole, risperidonerisperidone, or ziprasidone.ziprasidone.

45. Metabolic HighwayMetabolic Highway
Metabolically un friendly antipsychoticsMetabolically un friendly antipsychotics
Stahl S M, Essential Psychopharmacology (2002)

46. Avoiding Obesity
Weight gain increases not onlynot only the risk of diabetes,
but also of coronary artery disease, a variety of
cancers, gallbladder disease, gout, osteoarthritis,
sexual dysfunction, infertility, and sleep apnea.
Weight gain has a pronounced negative effectnegative effect on
self-esteem and affects compliance with
antipsychotics.

47. Stahl M.S. 2002: Psychopharmacology of antipsychotics
Weight gain
 (H1 & α1) antagonism
 5HT2c antagonism
 Dysregulation of leptin

48. Treating Patients With Sexual Dysfunction
Approximately halfhalf of all people taking antipsychotic
drugs complain about sexual dysfunction but the
mechanisms are poorly understood.
HyperprolactinemiaHyperprolactinemia seems to play a large part in
the causation.

49. Treating Patients With Sexual
Dysfunction cont’d
A decline in erectile frequency was found to
be especially prevalentespecially prevalent in patients treated
with risperidonerisperidone.
Women's sexuality is as affected as that ofWomen's sexuality is as affected as that of
men.men.

50. Treating Treatment-Refractory Patients
While all the new drugs have been alleged to show superior efficacy
to the older drugs, this claim has only been convincingly
substantiated for clozapineclozapine .
This poses a problem for patients with a personal or family historypersonal or family history
of type 2 diabetes or cardiovascular illnessof type 2 diabetes or cardiovascular illness who have not
responded to standard treatment (so, monitor of cholesterol, triglyceridesmonitor of cholesterol, triglycerides
and sugar levelsand sugar levels).

51. Treating Women (Pregnancy)
FDA: “Use in Pregnancy”- Drug categories
Category A: Controlled studies show no risk
Category B: No evidence of risk in humans
Category C: Risk to humans cannot be ruled out
Category D: positive evidence of risk but it is possible in some
situations the benefits may outweigh the risks {benifit > risk}
Category X: Toxic, Contraindicated in pregnancy. Risks
outweigh the benefits in almost every situation {risk > benifit}
A drug-free first trimester is ideal but not always achievable.

52. Because of rising estrogen levelsrising estrogen levels at this time and
estrogen modulation of the dopamine receptormodulation of the dopamine receptor, there
is relative protection against psychotic relapse .relative protection against psychotic relapse .
If antipsychotics are necessary, low-doselow-dose haloperidolhaloperidol
has the best safety record throughout pregnancy,
with dose reductiondose reduction priorprior to the anticipated day of
birth (to facilitate labor and minimize drug
withdrawal effects in the neonate).
Clozapine is unwise during pregnancyunwise during pregnancy because of the
theoretical possibility of seizure induction and
agranulocytosis in the fetus.
Treating Women (Pregnancy)

53. Treating Women (Lactation) cont’d
Breast feeding will mean that the baby is exposed to
the drug to some extent (infant sedation levels will need
monitoring).
No long-term developmentally adverse effects on
children exposed to the older antipsychotics.older antipsychotics.
Women with psychosis who may temporarily benefit
from high prolactin levelshigh prolactin levels (those who do not want to
conceive or, conversely, postpartum women whose milk is
insufficient for breast feeding) may preferentially benefit
from first-generation antipsychotics or risperidone.first-generation antipsychotics or risperidone.

54. Antipsychotics during adolescents
and childhood
A frequently used antipsychotic medication in the
treatment of Tourette’s is Risperdal and
Haloperidol .
Monitor for extrapyramidal symptoms, akathisia,
and acute dystonias as well as longer-term side
effects such as tardive dyskinesia and gynecomastia
in males.
Other atypical antipsychotics that have been used in
the treatment of Tourette’s Disorder include
Seroquel, Zyprexa, amd Aripiprazole.

55. Take-home MessagesTake-home Messages
• Conventional antipsychoticConventional antipsychotic drugs bind
tightly to the dopamine D2 receptors,
thereby eliciting EPS, elevated prolactinEPS, elevated prolactin
and tardive dyskinesia.and tardive dyskinesia.
• The atypical antipsychoticThe atypical antipsychotic attach more
loosely to the D2 receptors, thus resulting
in less or no EPS, elevation of prolactin,
and risk of tardive dyskinesia.

56. Past Areas of
Concern
Current Medical Realities
Shift in Risk PerceptionShift in Risk Perception
of Antipsychoticsof Antipsychotics
SedationWeight
Gain
Insulin
Resistance
CHD
Hyper-
lipidemia
Weight Gain
Diabetes
Prolactin
Insulin
Resistance
Sedation
Hyperlipidemia
Coronary Heart
Disease
Tardive
Dyskinesia
TD
Prolactin

57. Take-home MessagesTake-home Messages
Good clinical practice involves usinginvolves using
both typesboth types of medication at different
times, depending on the specific needs ofdepending on the specific needs of
the patientthe patient taking in consideration
Efficacy, Safety and Tolerability.

58. Future
Directions

59. diagnosisdiagnosis
trials and errorstrials and errors
effective treatmenteffective treatment
TODAY….TODAY….
TOMORROW….TOMORROW….
tailor madetailor made

60. Future of Behavioral Health has
Arrived
 Patients with depression and anxiety are frustrated with drug
treatments because of poor response (up to 5 trials).
 Also, some of these medications increase anxiety, resistance to
treatment, insomnia, and sexual dysfunction.
 Sometimes they may quit medications.
 It is better to choose psychotropic medications based on the individual
genetic characteristics, metabolizing pathways leading to better
medication tolerance.
 This give the patient the confidence to continue treatment.
 Test can done by a simple cheek swab (Assure Rx- GeneSightRx).

62. Future
 The FDA has approved several drug labels to contain information
about pharmacogenetic biomarkers.
 Currently, approximately 17% of these pharmacogenetic labels are for
psychiatric drugs, and most of them contain information about the
CYP450 enzymes.
 However, most of these labels do not offer any clinical
recommendations or require the use of this information before
treatment prescription.
 The ultimate goal of future studies is to expand the pharmacogenetic
information on antidepressant labels and incorporate them into wide
clinical use.
 However, there are several limitations that need to be considered
before the field can advance to this stage.

63. Probiotics
Probiotics may offer an alternative treatment
option for depression and other psychiatric
disorders, new research suggests.
Investigators reviewed studies that examined the
effect of "psychobiotics," live organisms that when
ingested may produce health benefits in patients
suffering from mental illness.

64. Probiotics
Several preclinical studies showed a link between
specific probiotics and beneficial behavioral
effects.
These included one in which rats with depressive
behaviors resulting from maternal separation
displayed normalized behavior and an improved
immune response after ingesting
the Bifidobacterium infantis probiotic.

65. Probiotics
Dr. Dinan noted that there are approximately 1 to
2 kg of bacteria in the adult gut that are capable
of producing hundreds of essential chemicals.
"Our preclinical studies suggest that depression is
also associated with an alteration in the
microbiota.
Psychobiotics are good bacteria that have the
potential to increase microbial diversity and treat
the symptoms of depression," he said.
The review is published in the November 15 issue
of Biological Psychiatry.

66. Hanipsych, art of antipsychotics