Psychotropics in Psychiatric Patient - Psychotic disorders: Pharmacology and Clinical Applications of Antipsychotics Pongsatorn Meesawatsom B. Pharm.,

Psychotropics in Psychiatric Patient - Psychotic disorders:

Pharmacology and Clinical Applications of Antipsychotics

Pongsatorn MeesawatsomB. Pharm., M.Sc. (Pharmacology)

Faculty of PharmacySrinakarinwirote University

Characteristics of schizophrenia

Prevalence 0.5–1.0% of populationOnset

Positive features in late adolescence or early adulthoodAspects of cognitive deficits detectable earlier in life

ComorbidityDepression: 30–50%∼Substance abuse: 50%∼Suicide: 5–10%∼

Schizophrenia: A Disease with Various Aspects

Positive SymptomsDelusions

HallucinationsDisorganized speech

Catatonia

Negative SymptomsAffective flattening

AlogiaAvolition

AnhedoniaSocial withdrawal

Cognitive DeficitsAttentionMemory

Executive functions(e.g., abstraction)

Mood SymptomsDepression

AnxietyAggression

HostilityHopelessness

Suicidality

Social/OccupationalDysfunction

WorkInterpersonal relationship

sSelf-care

Inter-relationship between disease factors and drug-induced adverse factors in the burden of schizophrenia

Int Clin Psychopharmacol 2005, 20:183–198.

Adverse effect of antipsychotic drugs

Risk of hyperglycemia/ diabetes

Other effects•Anticholinergic•Prolactin elevation•QTc prolongation

SedationExtrapyramidal

symptoms

Tardive dyskinesia

Weight gain

Suicidality

Dysphoria

Diverse symptoms of schizophrenia

Positive symptoms

Cognitive symptoms

Negative symptoms Depression/Anxiety

Disease factors

Drug-induced factors

Treatment Goal of Schizophrenia

Rapid symptom control

Acute Phase TreatmentAcute Phase Treatment Stabilization Phase Stabilization Phase TreatmentTreatment

Maintenance Phase Maintenance Phase TreatmentTreatment

Patient relationship Insight on medication

Relapse/recurrence prevention

Adherence Functional recovery

Initiation of therapeutically effective dose

No need for initial dose titration for tolerability

Minimal drug-drug interaction

Proven efficacy and safety

Increased tolerance to occasional missed doses

Proven relapse prevention effect

Improved PSP

Factors affecting antipsychotic response

Receptor pharmacology(binding capacity)

Pharmacokinetics Pharmacogenetics(CYP450)

Patient variables Comorbid condition/polypharmacy

The Dopamine hypothesis of psychosis

Overactivity of dopamine neurons in the mesolimbic dopamine pathway may mediate the positive symptoms

Dopamine hypocactivity in mesocortical dopamine pathway may mediate the negative and cognitive symptomsDorsolateral prefrontal cortex – negative, cognitive

symptomsVentromedial prefrontal cortex – negative, affective

symptoms

Brain dopaminergic tracts

11

22

33

44

6 Lateral hypothalamus6 Lateral hypothalamus5 CTZ5 CTZ

Simplify Neurocircuitry of Dopamine in Schizophrenia

DA

Mesolimbic pathwayHyperdopaminergia

D2

Positive symptoms

DA

Mesocortical pathwayHypodopaminergia

D1

Negative symptomsCognitive symptomsAffective symptoms

Limbic PFCx

Antipsychotic Drugs: Development Timeline

Minimal efficacy with regard to positive

symptoms in 20-30% of patients

Much weaker effect on negative

symptoms than positive symptoms

Significant parkinsonian symptoms and

anticholinergic effects (poor

compliance and potentially disabling)

Tardive dyskinesia in a minimum of

20% of patients who receive chronic

neuroleptic treatment.

At least as effective as typical

neuroleptics with regard to positive

symptoms

More effective than typical agents with

regard to negative symptoms

Much lower incidence of parkinsonian

symptoms and anticholinergic effects

than typical agents

TD does occur but at much lower

incidence

Elevated risk of metabolic side effects

Therapeutic effects from D2 receptor blockade

Amelioration of the positive signs, symptoms of psychosis, manic symptoms, aggressive behaviors

Antiemetic effect

Modified J Clin Psychiatry 1999;60(suppl 10):5–14.

Adverse effects from D2 receptor blockade

Extrapyramidal symptom (EPS)Acute; akathisia, acute dystonia, parkinsonism

Late; tardive dyskinesia

Endocrine effects: prolactin elevation

Weight gain due to increase feeding

Modified J Clin Psychiatry 1999;60(suppl 10):5–14.

Binding affinities of chlorpromazine and haloperidol for various receptor

J Psychiatr Pract 2005;11:258–61.

Higher potency

Higher EPS

Lower anticholinergic effect

Lower potency

Low EPS

Higher anticholinergic effect

HaloperidolFluphenazine

Trifluoperazine

Thioxanthine

Perphenazine

Pimozide

Chlorpromazine

Thioridazine

Mesoridazine

Rational explanations for SDA therapeutic effects

Therapeutic effects D2-receptor blockade in the mesolimbic pathway to reduce

positive symptomsEnhanced dopamine release and 5-HT2A receptor blockade

in the mesocortical pathway to reduce negative symptoms

Side-effect profile5-HT2A antagonism in the nigrostriatal pathway reduces EP

S and tardive dyskinesia5-HT2A antagonism in the tuberoinfundibular pathway reduc

es hyperprolactinemia

DA

D1D2

Caudate/putamen

Normal function

Sunstantia nigra pars

compacta

5-HT2A

-

5-HT

Raphe

5-HTT

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tract

DA

D1D2

Caudate/putamen

EPS

5-HT2A

-

5-HT

Raphe

5-HTT


Nigrostriatal tract

Haloperidol


compacta

DA

D1D2

Caudate/putamen

Less EPS

5-HT2A

-

5-HT

Raphe

5-HTT


Nigrostriatal tract

SDA


compacta

Modified from Clin Ther 2004;26:649-66

All values are reported as Ki (nM).

Receptor affinities of selected atypical antipsychotic

s

Receptor HAL CLOZ OLAN RIS QUET ZIP ARI

D2 0.7 126 11 4 160 5 0.45 (partial)

5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)

5-HT2A 45 16 4 0.5 295 0.4 3.4

5-HT2C 1500 16 23 25 1500 1 15

1 6 7 19 0.7 7 10 57

2 360 8 230 3 87 – –

H1 440 6 7 20 11 47 61

M1>1500 1.9 1.9 >10,000 120 >1,000 >10,000

Effects of blockade of neuroreceptors

Receptors Effects of blockade

D2 Anipsychotic, antimanic, antiaggressive, EPS/akathisia, tardive dyskinesia, increase prolactin, weight gain

5-HT1A Anxiolytic, antidepressant, anti-EPS/akathisia

5-HT2A Anti-EPS/akathisia, possible antipsychotics, improve REM sleep

5-HT2C Possible increased appetite/weight

Modified from J Clin Psychiatry 2008;69[suppl4]:26-36.



1 Postural hypotension, dizziness, syncope, nasal

congestion

2 Antidepressive effect, increase alertness,

increase blood pressure

H1 Anxiolytic, sedation, weight gain, potentiate CNS

depressant drug




M1

(central)

Memory dysfunction, delirium, confusion, sedation,

REM sleep disturbance , anti-EPS

M2, M3

(peripheral)

Blurred vision, attack or exacerbation of narrow-angle

glaucoma, dry mouth, sinus tachycardia, constipation,

urinary retention, interfere pancreatic insulin release


Impact of receptor binding affinity on clinical

responses of antipsychotics



Receptor affinities of selected atypical antipsychotics: Potential risk


D2 0.7 126 11 4 160 5 0.45 (partial)

5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)

5-HT2A 45 16 4 0.5 295 0.4 3.4

5-HT2C 1500 16 23 25 1500 1 15

1 6 7 19 0.7 7 10 57

2 360 8 230 3 87 – –

H1 440 6 7 20 11 47 61

M1 >1500 1.9 1.9 >10,000 120 >1,000 >10,000 Orthostatic

hypotension

Anticholinergics

Sedation, weight gainEPS risk and

hyperprolactinemia


Receptor affinities of selected atypical antipsychotics: Potential Benefit


D2 0.7 126 11 4 160 5 0.45 (partial)

5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)

5-HT2A 45 16 4 0.5 295 0.4 3.4

5-HT2C 1500 16 23 25 1500 1 15

1 6 7 19 0.7 7 10 57

2 360 8 230 3 87 – –

H1 440 6 7 20 11 47 61

M1 >1500 1.9 1.9 >10,000 120 >1,000 >10,000 PD psychosis BPSD, autism Sedative action


Sleep quality improvement

Alleviate EPS risk

*Receptor activity measured as inhibition of forskolin-induced cAMP accumulation in CHO cells transfected with human D2L DNA.

Adapted from Burris et al. J Pharmacol Exp Ther. 2002;302:381.

0

50

100

Drug Concentration

Max

imu

m D

A R

esp

on

se (

%)*

Dopamine

100 nM Dopamine+ Haloperidol

100 nM Dopamine+ Aripiprazole

Aripiprazole

10-10 10-9 10-8 10-7 10-6 10-5

Aripiprazole Activity at Cloned Human D2 Receptors

Haloperidol

Full Receptor Activity

PartialReceptor Activity

(Modulated)

No Receptor Activity

(Blocked)

Paliperidone vs Risperidone

Paliperidone is active metabolite of risperidone via metabolism by CYP2D6.

High affinity for D2, 5-HT2A, 1 and 22 receptors receptors

Very low affinity for M1 as same as as risperidone

Expert Opin Drug Saf. 2007 ;6(6):651-62.

Pharmacokinetics differences of risperidone and paliperidone

Risperidone Paliperidone

Tmax 1-2 hr (risperidone)

3 hr (paliperidone in CYP2D6 EM)

17 hr (paliperidone in CYP2D6 PM)

1-2 Hr (IR form)

24 hr (ER form)

T1/2 3 hr 23 hr (IR and ER

form)

Elimination

pathway

CYP2D6 to paliperidone (major)

CYP3A4 (minor) CYP3A4 to (minor)

inactive metabolite

and >80% found in

urine and

60%unchanged

Adverse Effect Profile of Antipsychotics

Past Areas of Concern

Current Medical Realities

Shift in Risk Perception of Antipsychotics

SedationWeight Gain

Insulin Resistance

CHD

Hyper-lipidemia

Weight Gain

Diabetes

Prolactin

Insulin Resistance

Sedation

Hyperlipidemia

Coronary HeartDisease

Tardive Dyskinesia

TD

Prolactin

D2 Blocking-related Side Effects

Spectrum of EPSL

ate

on

set

Acu

te

on

set

Acute dystonia

Relationship between clinical effectiveness, EPS and D2 receptor occupancy

Threshold for EPS

Threshold for antipsychotic

efficacy

80%

Medication used to treat EPS

Am J Health-Sys Pharm 1997;54:2461-77.

Association of medication, target dose, and likelihood of treatment-emergent EPS

J Psychiatric Pract 2007;13:13–24.

Tardive dyskinesia (TD)

TD is a latent extrapyramidal effect generally not occurring for months or years, occur in 20% patient treated with antipsychotic.

It is characterized by abnormal movements that can occur in any part of the body, including faces, tongue, shoulders, hips, extremities, fingers, and toes

Prominent Feature of TD

Lingual-facial hyperkinesias Chewing movements

Smacking and licking of the lips

Sucking movements

Tongue movements within the oral cavity

Tongue protrusion

Tongue tremor with mouth open

Myokemic movements (worm-like movement on the surface of the tongue)

Blinking

Grotesque grimaces and spastic facial distortions

Neck and trunk movements Spasmodic torticollis

Retrocollis

Torsion movements of the trunk

Axial hyperkinesia (hip-rocking)

Choreoathetoid movements of the extremities

Neuroleptic malignant syndrome

NMS is an uncommon but serious and potentially fatal complication of therapy

It is a syndrome of EPS, hyperthermia, altered consciousness, and autonomic changes (tachycardia, unstable BP, incontinence)

Management Discontinuation of the antipsychotic agents Supportive therapy Bromocriptine may be benificial

The onset is sudden and recovery may take 5-10 days after discontinuation of the agent

Simplified Pathophysiology of Neuroleptic Malignant Syndrome (NMS)

Am J Psychiatry 2007;164:870-876.

Spectrum-based concept of NMS

J Am Acad Child Adolesc Psychiatry 1992;31:1161–4.

Proposed Treatment Algorithm for NMS Spectrum-Related Symptoms

Am J Psychiatry 2007;164:870-876.

Hyperprolactinemia: possible signs and symptoms

J Clin Psychopharmacol 2007;27:639–661.

Osteoporosis

Mean Plasma Prolactin Level Changes Over 24 Hours in 18 Patients After Taking Clozapine, Olanzapine, or Risperidone and in Five of the Same Patients After Not

Taking the Drugs

Am J Psychiatry 2002; 159:133–135

Effects of Antipsychotics on Prolactin Levels

J Clin Psychopharmacol 2007;27:639–661.

Sedation

Receptor blocking properties that affect arousal and sleep stages

Blocking of H1 sedation

Blocking of M1 sedation, REM sleep

interference

Blocking of 1, 2, 5-HT2A promote cholinergic

pedunculopontine (PPT) and laterodorsal

tegmental nuclei (LDT) firing REM sleep

improvement

Clin Ther 2004;26:649-66All values are reported as Ki (nM).


s

Receptor HAL CLOZ RIS OLAN QUET ZIP ARI

D1 210 85 460 31 455 525 265

D2 0.7 126 4 11 160 5 0.45 (partial)

D3 2 473 10 49 340 7 0.8

D4 3 35 9 27 1600 32 44

5-HT1A 2600 875 210 >7100 >830 3 4.4 (partial)

5-HT2A 45 16 0.5 4 295 0.4 3.4

5-HT2C 1500 16 25 23 1500 1 15

1 6 7 0.7 19 7 10 57

2 360 8 3 230 87 – –

H1 440 6 20 7 11 47 61

M1>1500 1.9 >10,000 1.9 120 >1,000 >10,000

SGAs and sedation

J Clin Psychiatry 2008;69 Suppl 1:18-31.

Obesity and metabolic

syndromes

Clinical issues of weight gain and antipsychotics

Not everyone gains weight

Difficult to predict who will have weight

gain

Multifactorial etiology

Not dose related ADR.

Start in first few weeks

Reach plateau between 3 months to 1 year

Mean weight gain during treatment withantipsychotic drugs.

CNS Drugs 2005; 19 (Suppl. 1): 1–93.

Mechanisms of antipsychotic-induced weight gain and metabolic abnormalities

Interfere feeding behavior by blocking many

neuroreceptorFeeding center

Lateral hypothalamus (DA D2)

Ventromedial hypothalamus (5-HT 5-HT2A, 5-HT2C)

Satiety center

Paraventricular nuclei (NE 1, , Histamine H1)

Interfere pancreatic insulin release

Pancreas (ACh M3 )

AtropineAtropine OlanzapineOlanzapine ClozapineClozapine

ZiprasidoneZiprasidone RisperidoneRisperidone HaloperidolHaloperidol

Diabetes 2005; 54:1552–1558.

Clin Ther 2004;26:649-66All values are reported as Ki (nM).


s

Receptor HAL CLOZ RIS OLAN QUET ZIP ARI

D1 210 85 460 31 455 525 265

D2 0.7 126 4 11 160 5 0.45 (partial)

D3 2 473 10 49 340 7 0.8

D4 3 35 9 27 1600 32 44

5-HT1A 2600 875 210 >7100 >830 3 4.4 (partial)

5-HT2A 45 16 0.5 4 295 0.4 3.4

5-HT2C 1500 16 25 23 1500 1 15

1 6 7 0.7 19 7 10 57

2 360 8 3 230 87 – –

H1 440 6 20 7 11 47 61

M1>1500 1.9 >10,000 1.9 120 >1,000 >10,000

Olanzapine-Associated Weight Gain Plateaus After First 39 Weeks of Treatment

Kinon BJ, et al. J Clin Psychiatry 2001;62:92-100

Week

Mea

n W

eigh

t Cha

nge

(kg)

up

to 3

yea

rs

OLZ (N=573)

HAL (N=103)

-8 -6 -4 -2 0 2 4 6 8

0 20 40 60 80 100 120 140 160Patients Observed for 39 Weeks or More;Double-blind and open-label olanzapine.

LOCF; Median = 2.5 Years

Weight gain by olanzapine is

not dose dependent (5-20 mg dose range).

Why Less weight gain in quetiapine, ziprasidone and aripiprazole?

QuetiapineNorquetiapine inhibit

norepinephrine reuptake transporter

AripiprazoleLow affinity H1, 5-HT2C

Partial D2 agonist

ZiprasidoneModerate affinity for 1

Low affinity H1

Full 5-HT1A agonist

Inhibit 5-HT/NA reuptake transporter

SGAs and metabolic abnormalities

Clin Psy 2007;68(Suppl 7):27-33.

Monitoring protocol for patients on SDAs

Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years

Personal/family history ()Weight (BMI) () ()Waist circumference () () () () ()Blood pressure () () () ()Fasting

plasma glucose

() () () ()Fasting lipid profile () () ()

Diabetes Care 2004; 27(2): 596-601.

Other Adverse effects

QTC interval prolongationThioridazine, ziprasidone

AgranulocytosisClozapine

EpileptogenicClozapine

Retinitis pigmentosaThioridazine > 800 mg/day

Incidence of categorical increases in QTc (Bazett correction)

There is a consensus that a QTc interval of >500ms, or an absolute in-crease of 60ms compared with drug-free baseline, puts a patient at significant risk of torsade depointes, ventricular fibrillation and sudden death

Clozapine safety issues

Clozapine is one of the atypical agents that is EPS/TD free, as same as quetiapine

However, clozapine is still reserved as last-line therapy because of its increased incidence of agranulocytosis, myocarditis/cardiomyopathy, and convulsion and the need for frequent monitoring

Clozapine safety issues

Seizure risk1-2% and increase to 3-5% if dose is greater than 600

mg/day.

Agranulocytosis1% in general95% cases in first 6 m,

peak in 4-18 week CBC weekly

Management of clozapine-induced agranulocytosis

US

New patients: weekly blood

counts

Twice weekly monitoring: WBC

3000-3500 and ANC >1500

Temporary discontinuation: WBC

2000-3000 and/or ANC 1000-

1500

Permanent discontinuation: WBC

<2000 and/or ANC <1000

> 6 months: monitor once every

two weeks

UK

New patients: weekly blood

counts

Weekly monitoring: WBC 3000-

3500 and/or ANC1500-2000

Discontinue: WBC <3000 and/or

ANC ≤1500

Weeks 19-52: at least every 2

weeks

> 52 weeks: monitor at least

monthly thereafter

Contribution of CYP450 in atypical antipsychotic drug metabolism

DrugCYP450

1A2 2C9/2C19 2D6 3A4

Aripiprazole Clozapine Olanzapine /-

Paliperidone

/-

Quetiapine Risperidone Ziprasidone

(1/3 with

aldehyde oxidase)

Enzyme Substrate Inhibitor Inducer

CYP1A2 Clozapine, olanzapine Fluvoxamine, ciprofloxacin

Carbamazepine, smoking

CYP2C19 Fluoxetine, fluvoxamine Carbamazepine, phenytoin

CYP2D6 Aripiprazole, clozapine, olanzapine, risperidone, conventional antipsychotics

Bupropion, fluoxetine, paroxetine, duloxetine

CYP3A4 Aripiprazole, clozapine,, quetiapine, ziprasidone

Azole antifungalMost of macrolide except

azitromycinARVs; indinavir,

nelfinavir, ritonavir

Carbamazepine,phenytoin, rifampin, phenobarbital

Dose-response curve for seizure risk with clozapine

Dose-response curve for extrapyramidal adverse effects with risperidone

J Psychiatric Pract 2005;11:116-122.

Acute treatment of psychoticpatients

Injectable, conventional agents are typically used such as haloperidol 5-10 mg IM or zuclopenthixol acetate 50150mg

It may be given every hour untilAcute symptoms are controlled

Side effects occur

Patient falls asleep

Once control has been obtained, the patient can be converted to oral therapy

Selection of antipsychotic agents

Based on the patient’s history and safety profile of the available agents

Newly diagnosed patients, the APA suggest initiating therapy with atypical agent (SGAs) because of these agents’improve safety profile

Monitoring of first episode

Less disturbed sleep patterns and decreased anger and anxiety should be observed within the first day or two of treatment, with gradual improvement in other symptoms in the first week and near-maximal effects in six to eight weeks

Lack of improvement in the first one to four weeks should prompt an increase in the dose, followed by a change to another drug, usually clozapine or another second-generation drug after an additional four to six weeks, if the response remains inadequate

N Eng J Med 2003;349:1738-49.

Monitoring of early adverse effects

It appears within days to weeks of starting the antipsychotic dose

It maybe transient and time limited (it will be disappear after the first month of treatment)

J Clin Psy 2007;68(Suppl 7):34-43.

Initial dose and titrationschedule for a firstepisode

J Clin Psy 2007;68(Suppl 7):3443.

Strategies for managing side effects in stable patients

J Clin Psy 2007;68(Suppl 7):34-43.

Medical Issues in Schizophrenia

Factor Prevalence in Schizophrenia

Prevalence in

General Population

Smoking 75% 25%

Obesity 50% 33%

Diabetes Mellitus 13-14% 7%

HIV 3% 0.3%

Hepatitis C 20% 1.8%

Other:

-inactivity, poor nutrition

-substance use

Meyer JM and Nasrallah H eds. Medical Illness and Schizophrenia. APPI 2003Regenold WT, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective disorders independent of psychotropic drug use. Journal of Affective Disorders. 2002 Jun;70(1):19-26

Medical conditions that may influence antipsychotic treatment dicisions

Antipsychotics switching

Avoid if possibleConsider in

Not responing patient with adequate trialNot able to tolerateNon-compliance (switch to depot preparation)Significant long term risk with current medication

Obesity, TD, persistent cognitive deficit, CVS problems, DDI

Patient/family member request

Switching techniques for antipsychotics

CNS Drugs 2005; 19 (1): 27-42

Dopaminergic considerations

Cross switching of 2 high potency D2

antagonist may increase EPS risk.

J Clin Psy 2007;68(Suppl 7):109.

Dopaminergic considerations

Prolong exposure of high potency D2 antagonist

results in D2 supersensitivity

Switching D2 antagonist from higher potency to

lower potency or D2 partial agonist

May lead to switch-emergent dopamine psychosis.

Improvement in prolactin-related side effects such as galactorrhea, amenorrhea and sexual dysfunction and EPS

Muscarinic considerations

There is a potential that patient who have been maintained on anticholinergic antipsychotics to develop cholinergic supersensitivity.

Nausea, vomiting and insomnia may occur when anticholinergic drugs is withdrawn or switched to less potent anticholinergic drugs.

Muscarinic considerations

If patient is being changed because of EPS in which an anticholinergic agents was initiated, the patient can remain on the anticholinergic agent until the cross taper and titrated is completed

Exception in the case of clozapine being added as the new therapy, the anticholinergic drugs should be discontinued when the cross taper and titration begins

Estimated side effects after switching

J Clin Psy 2008;69(Suppl 1):4-17.

Conclusions

Antipsychotics are not uniform drug class which different in their pharmacological profile, efficacy and ADRs.

Adherence of treatment should be enhanced by various strategies e.g.Counseling Awareness of DDIADR monitoring and management

Documents

Psychotropics in Psychiatric Patient - Psychotic disorders: Pharmacology and Clinical Applications of Antipsychotics Pongsatorn Meesawatsom B. Pharm.,