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Hani hamed dessoki art, antipsychotic
1.
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
5. Developments in the Treatment
of Schizophrenia
’30s
’40s
’50s
’60s
Haloperidol
Electroconvulsive Fluphenazine
Thioridazine
therapy
Loxapine
Perphenazine
Chlorpromazine
First Generation
Antipsychotics
(FGAs)
’70s
’80s
’90s & ’00
’06-’08
Clozapine Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Asenapine
Bifeprunox
Paliperidone
Iloperidone
Second Generation
Antipsychotics
(SGAs)
6. Introduction
Knowing how 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 efficacy in countering
psychotic symptoms.
7. Principles of Antipsychotic Access,
Efficient Utilization and Prescribing
1.
Treatment with antipsychotic medications, like any
other treatment, should be individualized in order to
optimally promote recovery.
2.
Treatment with antipsychotic medication should be
as effective, safe and well-tolerated as possible.
3.
Treatment with antipsychotic medication should
consider personal preference and vulnerabilities.
8. Principles cont’d
4. Treatment with antipsychotic medication should
provide value in terms of improved quality of
life to the consumer.
5. Treatment choices should be informed by the
best current evidence and must evolve in
response to new information.
6. Cost considerations should guide
antipsychotic medication selection if the
preceding principles are met.
9. 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)
Agonist
Partial
Agonist
Antagonist
Inverse
Partial
Agonist
Inverse
Agonist
12. loosely bound;
fast release from
receptor
tightly bound;
slow release
from receptor
DA receptor
Drug
psychlotron.org.uk
Typical vs. atypical
13. Difference Between Low and High
States cont’d
The affinity, or more precisely, the dissociation
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 antipsychotics generally have
dissociation constants lower than 1.75 nM, which
means that they are more tightly bound to D2
compared with dopamine.
14. Does 65% Occupancy Need to Be
Maintained Full Time? (cont.)
The new so-called atypical antipsychotics, such as
clozapine, quetiapine, amisulpride, and remoxipride
merely "block and run” (but at different speeds).
For instance, the atypical, sertindole, and olanzapine, dissociates
from the D2 receptor more slowly than clozapine or quetiapine, but
more quickly than haloperidol or chlorpromazine.
15. Relative Binding of Antipsychotics
To D2 Receptors
K at D2 (nM)
100
10
Quetiapine
Clozapine
Olanzapine
Sertindole
“Loose”
“Intermediate”
Dopamine K (1.5nM)
1
Risperidone
Ziprasidone
Chlorpromazine
Haloperidol
Fluphenazine
0.1
“Tight”
16. Relevant Occupancy
The blockade needed to alleviate psychotic
symptoms is approximately two thirds or 65% of
the population of D2 receptors (e.g. basal ganglia
or striatum).
When fewer than 60% of receptors are occupied
(ie, when subthreshold doses are prescribed or
when medication is not taken as prescribed), the
symptoms of psychosis return.
17. Motor Side Effects
The emergence of motor side effects with using of
typical antipsychotics depends on the exact
percentage of occupied D2 receptors (80%
occupancy of D2).
However, patients on the new atypical compound,
Sertindole and aripiprazole, may not exhibit
parkinsonism even with 90% occupation of D2
receptors.
18. Motor Side Effects (Cont.)
In general, for first-generation antipsychotics, the
effective dose range before motor side effects set is
relatively narrow.
So raising the dose of haloperidol, for instance,
from 2 mg per day to 4 mg per day may
overshoot the 80% occupancy place a patient over
the threshold for the development of EPS.
19. Does 65% Occupancy Need to Be Maintained
Full Time? (cont.)
Brain imaging studies indicate that the traditional
antipsychotics stay attached to dopamine D2
receptors for at least 1 or 2 days following an oral
dose (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 the
development of tardive dyskinesia.
20. Does 65% Occupancy Need to Be Maintained
Full Time? cont’d
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.
21. Why Psychotic Symptoms Wane With
Age?
Under untreated conditions, the number of
receptors diminishes as the person ages.
This explains, perhaps, the age-related reduction of speed of
arousal, of peaks of pleasure, of frequency of impulsive behavior -all experiences mediated by dopamine.
22. Why Higher Doses Are Required Over
Time
In patients treated over long periods of time with
antidopaminergic drugs, receptor proteins adapt
to blockade by creating more D2 receptors
(receptor proliferation).
So that, in chronically treated schizophrenia
patients, receptor numbers rise and
maintenance doses increase at the same time.
23. Choosing antipsychotic & why?
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.
24. Choosing antipsychotic & why?
(cont.)
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
25. 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.
The therapeutic concentration of the antipsychotic in
the presence of abundant dopamine will need to be
proportionally higher than that needed in periods of
calm.
26. Treating First Episodes
Young patients with a first episode of psychosis
respond equally well to first- and secondgeneration drugs, but tolerability of the drug regime
is especially important in this population.
27. Treating Non Adherent Patients
Patients known to be non adherent to regular
medication will do better on those drugs that are
relatively tightly bound to the D2 receptor (where
relapse due to a brief period of noncompliance is a lesser risk).
Monthly depot medication is still the treatment of
choice for the extremely non adherent.
28. Problems Hinder Achieving
Non adherence to treatment
41% Compliant
39%
Non- compliant
20%
Partially compliant
Medication compliance is poor in
patients with Schizophrenia
Coldham EL, et al. Acta Psychiatr Scand 2002;106:286–90
29. NICE guidelines;
For people with newly diagnosed (first episode)
schizophrenia,
National Clinical Practice Guideline Number 82. National Institute
for Health and Clinical Excellence 2009.
30. 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.
This is especially 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/L.
31. Potential consequences of prolactin
elevation
Erectile
dysfunction
Amenorrhoea
Gynaecomastia
Loss of libido
Impotence
Prolactin
Elevation
Osteoporosis
bone density
Galactorrhoea
32. Treating Cardiac Patients or Those With a Family
History of Cardiac Disease
The QTc interval (approximate range is 350-440 milliseconds [ms])
represents the duration of ventricular depolarization and repolarization.
It is generally accepted that QTc intervals exceeding 500 ms are associated
with an increased risk of a lethal paroxysmal ventricular tachycardia
(torsades de pointes).
34. 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 higher than in the general
population, probably because of relative inactivity
and the high prevalence of smoking, poor diet and
obesity.
35. 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;
sertindole, risperidone and ziprasidone are
associated with lower rates.
Patients with a family history of diabetes and with
other concurrent risk factors should be treated with
sertindole, risperidone, or ziprasidone.
36. Metabolic Highway
Stahl S M, Essential Psychopharmacology (2002)
Metabolically un friendly antipsychotics
37. Avoiding Obesity
Weight gain increases not 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 effect on
self-esteem and affects compliance with
antipsychotics.
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40. Treating Patients With Sexual Dysfunction
Approximately half of all people taking antipsychotic
drugs complain about sexual dysfunction but the
mechanisms are poorly understood.
Hyperprolactinemia seems to play a large part in
the causation.
41. Treating Patients With Sexual
Dysfunction cont’d
A decline in erectile frequency was found to
be especially prevalent in patients treated
with risperidone.
Women's sexuality is as affected as that of
men.
42. Sertindole
• Sertindole is not associated with decreased libido, erection or
orgasm
• This is due to its ability to maintain prolactin levels within
normal limits
• 22% of male sertindole patients experience a decreased
ejaculatory volume (DEV)
• However, a discontinuation rate of 3% due to DEV indicates
that DEV is not a barrier to continuing treatment
• Sertindole does not cause decreased fertility
van Kammen 1996, Kasper 2002,
Summary of product characteristics 2010
43. 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 clozapine .
This poses a problem for patients with a personal or family history
of type 2 diabetes or cardiovascular illness who have not
responded to standard treatment (so, monitor of cholesterol, triglycerides
and sugar levels).
44. 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.
45. Treating Women (Pregnancy)
Because of rising estrogen levels at this time and
estrogen modulation of the dopamine receptor, there
is relative protection against psychotic relapse .
If antipsychotics are necessary, low-dose haloperidol
has the best safety record throughout pregnancy,
with dose reduction prior to the anticipated day of
birth (to facilitate labor and minimize drug
withdrawal effects in the neonate).
Clozapine is unwise during pregnancy because of the
theoretical possibility of seizure induction and
agranulocytosis in the fetus.
46. 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.
Women with psychosis who may temporarily benefit
from high 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.
47. 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.
48. When Serdolect???
Patients are likely to benefit from Sertindole:
If positive/negative symptoms are not controlled
If sedation, EPS or TD are present
If they experience excessive weight gain
If they are experiencing anticholinergic side effects
If their sexual functioning is impaired
If their cognitive function is impaired
49. Take-home Messages
• Conventional antipsychotic drugs bind
tightly to the dopamine D2 receptors,
thereby eliciting EPS, elevated prolactin
and tardive dyskinesia.
• The atypical antipsychotic attach more
loosely to the D2 receptors, thus resulting
in less or no EPS, elevation of prolactin,
and risk of tardive dyskinesia.
50. Shift in Risk Perception
of Antipsychotics
Past Areas of
Concern
Current Medical Realities
Diabetes
Weight Gain
Weight
Gain
Sedation
Tardive
Dyskinesia
Insulin
Resistance
CHD
Prolactin
Hyperlipidemia
Prolactin
TD
Hyperlipidemia
Insulin
Resistance
Sedation
Coronary Heart
Disease
51. Take-home Messages
Good clinical practice involves using
both types of medication at different
times, depending on the specific needs
of the patient taking in consideration
Efficacy, Safety and Tolerability.
54. 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).
55.
56. 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.
57. 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.
58. 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.
"
59. 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.
