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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

Schizophrenia Core Symptoms

Psychotic Deficit Cognitive

PositiveSymptoms

Mesolimbic pathway

NegativeSymptoms

DLPC &VMPFC

CognitiveDysfunction

DLPFC

AffectiveVMPFC

Mesocortical /prefrontal cortex

Symptoms May Match To Malfunctioning Brain Circuits

)Conlry.R, 2007(

Positivesymptoms

Mesolimbic

Negativesymptoms

Nucleus accumbens reward circuits

Cognitivesymptoms

Dorsolateral prefrontal cortex

Dopamine

Aggressivesymptoms

AmygdalaOrbitofrontalcortex

Affectivesymptoms

VentromedialPrefrontalcortex

Then and Now: The Evolution of Antipsychotics

Preskorn SH. Psychiatr Pract. 2001 ;7(3):209-13.

1950sMultiple mechanisms of action(eg. chlorpromazine)

1990sMultiple mechanisms of action(„atypical” antipsychotics)

1970sSingle mechanism of action(eg. haloperidol)

AsenapineAsenapine

BifeprunoxBifeprunox

PaliperidonePaliperidone

IloperidoneIloperidone

’’30s ’40s ’50s ’60s30s ’40s ’50s ’60s ’70s ’80s ’90s & ’00 ’70s ’80s ’90s & ’00 ’06-’08 ’06-’08

ElectroconvulsiveElectroconvulsive therapy therapy

ChlorpromazineChlorpromazine

Haloperidol Haloperidol FluphenazineFluphenazineThioridazineThioridazineLoxapineLoxapinePerphenazinePerphenazine

First Generation First Generation Antipsychotics Antipsychotics (FGAs)(FGAs)

Second Generation Second Generation Antipsychotics Antipsychotics (SGAs)(SGAs)

Risperidone Risperidone OlanzapineOlanzapineQuetiapineQuetiapineZiprasidoneZiprasidoneAripiprazoleAripiprazole

Developments in the Treatment of Schizophrenia

ClozapineClozapine

The Concept of Treatment Effectiveness

Efficacy Tolerability

Adherence/Persistence

TreatmentEffectiveness

Lehman AF, et al. Am J Psychiatry 2004;161(suppl 2):1-56.Swartz MS, et al. Schizophr Bull 2003;29(1):33-43.

Terminology of “Treatment Response”

Term Symptom reduction

Adverse effect & Tolerability

Cost

a)-Efficacy: + - -

b)-Effectiveness : + + -

c)-Efficiency : + - +

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.

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

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

quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, α1, α2, H1

aripiprazole D2, 5-HT2A, 5-HT1A, α1, α2, H1

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.

Principles cont’d

4. Treatment with antipsychotic medication should provide value in terms of improved quality of improved 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.

Clinical Decision Making:Weighing Risks and Benefits

DiscontinueManage adverse events vs. Discontinue?

Intolerable

Adverse Events

Discontinue vs. Augment?

Continue current therapy

Tolerable

Adverse Events

Poor ResponseGood Response

DiscontinueManage adverse events vs. Discontinue?

Intolerable

Adverse Events

Discontinue vs. Augment?

Continue current therapy

Tolerable

Adverse Events

Poor ResponseGood Response

AntagonistPartial

AgonistAgonist Antagonist

InversePartial

AgonistPartial

AgonistInverseAgonistAgonist

Binding to Receptors

Agonists & Antagonists bind competitively - beware misunderstandingsfrom binding data without further functional analysis

Endogenous agonists often bind weakly (enthalpy driven)

Successful antagonists often bind tightly (entropy driven)

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

AntagonistPartial Agonist

Inverse Agonist

log [Ligand] (M)

Rec

epto

r A

ctiv

ity

Typical vs. atypical

psyc

hlot

ron.

org.

uk

The affinity, or more precisely, the dissociation dissociation 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

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.

Relative Binding of AntipsychoticsTo D2 Receptors

Quetiapine

Clozapine

Olanzapine

Sertindole

Risperidone

Ziprasidone

Chlorpromazine

Haloperidol

Fluphenazine

“Loose”

“Intermediate”

Dopamine K (1.5nM)

“Tight”

K a

t D

2 (n

M)

100

10

1

0.1

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), the the symptoms of psychosis return.symptoms of psychosis return.

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.

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 overshoot overshoot the 80%80% occupancy place a patient over the threshold for the development of EPS.

Motor Side Effects (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 at 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 the is probably responsible for the development of tardive dyskinesia.development of tardive dyskinesia.

Does 65% Occupancy Need to Be Maintained Full Time? (cont.)

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

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.

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.

� 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?

� 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.)

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.

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.

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.

Problems Hinder Achieving Problems Hinder Achieving

Non adherence to treatment

Medication compliance is poor inpatients with Schizophrenia

Medication compliance is poor inpatients 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

NICE guidelines;For people with newly diagnosed (first episode) schizophrenia,

National Clinical Practice Guideline Number 82. National Institute

for Health and Clinical Excellence 2009.

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.

Potential consequences of prolactin Potential consequences of prolactin elevationelevation

Amenorrhoea

Loss of libidoImpotence

Erectile dysfunction

Osteoporosis bone density

Prolactin Elevation

Gynaecomastia

Galactorrhoea

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).

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

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.

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.

Metabolic HighwayMetabolic Highway

Metabolically un friendly antipsychoticsMetabolically un friendly antipsychoticsStahl S M, Essential Psychopharmacology (2002)

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.

Stahl M.S. 2002: Psychopharmacology of antipsychotics

Weight gain

(H1 & α 1) antagonism

5HT2c antagonism

Dysregulation of leptin

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.

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 of Women's sexuality is as affected as that of men.men.

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 history personal 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, triglycerides monitor of cholesterol, triglycerides

and sugar levelsand sugar levels).

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.

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-dose low-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)

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.

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.

Take-home MessagesTake-home Messages

• Conventional antipsychoticConventional antipsychotic drugs bind tightly to the dopamine D2 receptors, thereby eliciting EPS, elevated prolactin EPS, 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.

Past Areas of Concern

Current Medical Realities

Shift in Risk Perception Shift in Risk Perception of Antipsychotics of Antipsychotics

SedationWeight Gain

Insulin Resistance

CHD

Hyper-lipidemia

Weight Gain

Diabetes

Prolactin

Insulin Resistance

Sedation

Hyperlipidemia

Coronary HeartDisease

Tardive Dyskinesia

TD

Prolactin

Take-home MessagesTake-home Messages

� Good clinical practice involves using involves using both typesboth types of medication at different times, depending on the specific needs of depending on the specific needs of the patient the patient taking in consideration Efficacy, Safety and Tolerability.

Future Directions

diagnosisdiagnosistrials and errorstrials and errors effective treatmenteffective treatment

TODAY….TODAY….

TOMORROW….TOMORROW….

tailor madetailor made

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).

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.

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.

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.

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.

Hanipsych, art of antipsychotics