Antipsychotic TreatmentAntipsychotic Treatment

Monica RamirezMonica Ramirez

Medicinal ChemistryMedicinal Chemistry

March 30, 2006March 30, 2006

Psychotic Disorders

Definition: Psychotic disorders are defined as mental disorders in which the personality is severely altered and a person’s contact with reality is impaired. Characteristics: delusions, hallucinations, odd behavior, and incoherent or disorganized speech

Causes: Traumatic Experience, Stressful Event, and Drug Use

Major Psychotic DisordersMajor Psychotic Disorders

Brief Psychotic Disorder Brief Psychotic Disorder Delusional DisorderDelusional Disorder Schizoaffective DisorderSchizoaffective Disorder SchizophreniformSchizophreniform Shared Psychotic Disorder Shared Psychotic Disorder SchizophreniaSchizophrenia

Treatment Before Drugs Came into PlayTreatment Before Drugs Came into Play

Patients were kept isolated from everybody else.Patients were kept isolated from everybody else. Shock Treatment: consisted of Shock Treatment: consisted of twirling patients twirling patients

on a stool until they lost consciousness or on a stool until they lost consciousness or dropping them through a trap door into an icy dropping them through a trap door into an icy lakelake

Insulin-Shock Therapy: consisted Insulin-Shock Therapy: consisted injecting insulin injecting insulin into the patient until he or she became into the patient until he or she became hypoglycemic enough to lose consciousness and hypoglycemic enough to lose consciousness and lapse into a comalapse into a coma

InstitutionalizedInstitutionalized

Anti-psychotic DrugsAnti-psychotic Drugs

Antipsychotic drugs (also known as Antipsychotic drugs (also known as major tranquilizers because they major tranquilizers because they tranquilize and sedate) mitigate or tranquilize and sedate) mitigate or eliminate the symptoms of psychotic eliminate the symptoms of psychotic disorders but they do not cure them. disorders but they do not cure them.

Antipsychotic drugs were initially called Antipsychotic drugs were initially called neuroleptics because they were found to neuroleptics because they were found to cause neurolepsy, which is an extreme cause neurolepsy, which is an extreme slowness or absence movement.slowness or absence movement.

New Era in Psychiatric New Era in Psychiatric MedicineMedicine

• Chlorpromazine was the Chlorpromazine was the

first anti-psychotic drug first anti-psychotic drug

developed developed • Initially this drug was Initially this drug was

administered toadministered to

patients before a surgery because patients before a surgery because it it

produced anti- anxiety effects. It produced anti- anxiety effects. It waswas

then tried on patients with mental then tried on patients with mental

illnesses and it was discovered illnesses and it was discovered thatthat

it relieved psychotic episode it relieved psychotic episode symptoms.symptoms.

PhenothiazinesPhenothiazines Chlorpromazine belongs to this class Chlorpromazine belongs to this class

of drugs.of drugs. Other examples include:Other examples include:

Fluphenazine

Perphenazine

Trifluoperazine

Mechanism of Action of Mechanism of Action of PhenothiazinesPhenothiazines

The drugs found in this class are The drugs found in this class are antagonists.antagonists.

They work by blocking the D2 receptors They work by blocking the D2 receptors in the dopamine pathways of the brain; in the dopamine pathways of the brain; thus, decreasing the normal effect of thus, decreasing the normal effect of dopamine release.dopamine release.

Blocking the D2 receptors in the Blocking the D2 receptors in the mesolimbic pathway results in the mesolimbic pathway results in the antipsychotic effect.antipsychotic effect.

Side Effects Associated Side Effects Associated with Phenothiazineswith Phenothiazines

• PharmacologicPharmacological Side Effectsal Side Effects• ConstipationConstipation• Retention of urineRetention of urine• Increased heart Increased heart

raterate• Dry mouthDry mouth• Dilated pupils Dilated pupils

Serious Side Serious Side EffectsEffects

•Parkinsonianlike Parkinsonianlike syndromesyndrome

•DystoniaDystonia•Diskinesia Diskinesia •Neuroleptic Neuroleptic

Malignant Malignant Syndrome (NMS)Syndrome (NMS)

ButyrophenonesButyrophenones

Butyrophenones are high-potency Butyrophenones are high-potency antipsychotics (potency refers not antipsychotics (potency refers not to effectiveness but rather to the to effectiveness but rather to the ability to bind to dopamine ability to bind to dopamine receptors)receptors)

Haloperidol (Haldol) is the most Haloperidol (Haldol) is the most common of the butyrophenones: common of the butyrophenones:

Other ButyrophenonesOther Butyrophenones

DroperidolDroperidol

BenperidolBenperidol

Mechanism of ActionMechanism of Action All the butyrophenones work in the All the butyrophenones work in the

same manner as the phenothiazines.same manner as the phenothiazines.

They block the D2 receptors in the They block the D2 receptors in the dopamine pathways, thus, thwarting dopamine pathways, thus, thwarting any possible over excitation of the any possible over excitation of the dopamine receptors. dopamine receptors.

Side Effects of Butyrophenones

Pharmacological effects includePharmacological effects include::– Dry mouthDry mouth– Urinary retentionUrinary retention– Dimmed sightDimmed sight

More Serious Side effects More Serious Side effects includeinclude::

-Dystonia-Dystonia-Tardive Dyskinesia-Tardive Dyskinesia- Akathisia - Akathisia

Comparisons Between the Comparisons Between the Two Classes of DrugsTwo Classes of Drugs

PhenothiazinesPhenothiazines– Low potency Low potency – Are sedative Are sedative – Block D2 receptorsBlock D2 receptors– metabolism and metabolism and

removal of removal of phenothiazines is phenothiazines is complex and among complex and among the slowest of any the slowest of any group of drugs group of drugs

– cause extra cause extra pyramidal symptoms pyramidal symptoms

ButyrophenonesButyrophenones– High potencyHigh potency– Non-sedativeNon-sedative– Block D2 receptorsBlock D2 receptors– Metabolism and Metabolism and

removal is quicker removal is quicker – Cause extra Cause extra

pyramidal pyramidal symptomssymptoms

Typical AntipsychoticsTypical Antipsychotics Phenothiazines and Butyrophenones are typical Phenothiazines and Butyrophenones are typical

antipsychoticsantipsychotics These drugs are no longer regarded as the best These drugs are no longer regarded as the best

practice for treating psychotic disorders, even practice for treating psychotic disorders, even though they are still commonly utilized in though they are still commonly utilized in emergency treatmentsemergency treatments. .

The reason for this is that they are not very The reason for this is that they are not very selective. They do not only block the D2 receptors selective. They do not only block the D2 receptors of the mesolimbic pathway but also block the D2 of the mesolimbic pathway but also block the D2 receptors in the nigrostriatal pathway, mesocortical receptors in the nigrostriatal pathway, mesocortical zone, and tuberoinfundibular pathway.zone, and tuberoinfundibular pathway.

The fact that they are not very selective causes the The fact that they are not very selective causes the extra pyramidal symptoms such as tardive diskinesiaextra pyramidal symptoms such as tardive diskinesia

Atypical Anti-psychoticsAtypical Anti-psychotics

Were developed in an attempt to minimize Were developed in an attempt to minimize the side effects of typical anti-psychoticsthe side effects of typical anti-psychotics

They have proven to cause fewer extraThey have proven to cause fewer extra

pyramidal symptoms (EPS) when compared pyramidal symptoms (EPS) when compared

to typical anti-psychotics. to typical anti-psychotics. They produce fewer EPS because they are They produce fewer EPS because they are

more selective. more selective.

Common Atypical Common Atypical AntipsychoticsAntipsychotics

ClozapineClozapine

RisperidoneRisperidone

OlanzapineOlanzapine

Other Atypical AntipsychoticsOther Atypical Antipsychotics

Quetiapine:Quetiapine:

Ziprasidone:Ziprasidone:

Mode of ActionMode of Action Antagonists Antagonists Atypical antipsychotic drugs have a similar Atypical antipsychotic drugs have a similar

blocking effect on D2 receptors but appear blocking effect on D2 receptors but appear to be more selective in targeting the to be more selective in targeting the intended pathway to a larger degree than intended pathway to a larger degree than typical antipsychotics.typical antipsychotics.

They also interact with other They also interact with other neurotransmission systems, particularly neurotransmission systems, particularly with the serotonergic and noradrenergic with the serotonergic and noradrenergic pathways.pathways.

Side Effects Associated with Side Effects Associated with AtypicalAtypical

AntipsychoticsAntipsychotics Glucose Metabolism Disorders such as hyperglycemia, Glucose Metabolism Disorders such as hyperglycemia, onset of diabetes type 2, and worsening of pre-onset of diabetes type 2, and worsening of pre-existing diabetes ( This was particularly seen with existing diabetes ( This was particularly seen with patients treated with olanzapine and clozapine)patients treated with olanzapine and clozapine)

Weight Gain has been seen with patients taking Weight Gain has been seen with patients taking Olanzapine; the increase of weight gain can result in Olanzapine; the increase of weight gain can result in other heart diseases such as hypertension and other heart diseases such as hypertension and coronary heart disease.coronary heart disease.

QTc prolongation which QTc prolongation which occurs when there is an occurs when there is an abnormally long delay between the electrical abnormally long delay between the electrical excitation and relaxation of the ventricles of the heart excitation and relaxation of the ventricles of the heart which can cause deathwhich can cause death

Most Common Problems Most Common Problems Associated with Antipsychotic Associated with Antipsychotic

TreatmentTreatment•The slow onset of antipsychotic The slow onset of antipsychotic

efficacyefficacy•The development of The development of

antipsychotic-induced side effectsantipsychotic-induced side effects•Patients’ vulnerability to relapse Patients’ vulnerability to relapse

following antipsychotic drug following antipsychotic drug discontinuation. discontinuation.

Current and Future Work in Current and Future Work in Antipsychotic TreatmentAntipsychotic Treatment

• Synthesis of compounds acting on N-Methyl-Synthesis of compounds acting on N-Methyl-D-Aspartate (NMDA) sub-group of glutamate D-Aspartate (NMDA) sub-group of glutamate receptors, which are believed to be involved receptors, which are believed to be involved in the pathogenesis of psychotic in the pathogenesis of psychotic symptomatology.symptomatology.

• Aripiprazole is a new atypical antipsychotic Aripiprazole is a new atypical antipsychotic drugdrug thatthat shows both partial agonist activity shows both partial agonist activity at the D2 and 5HT1A receptors and potent at the D2 and 5HT1A receptors and potent antagonism activity at the 5HT2A receptors. antagonism activity at the 5HT2A receptors.

• Individualized treatment based on genetic Individualized treatment based on genetic profile in attempts to eliminate side effects profile in attempts to eliminate side effects

ReferencesReferences

• http://en.wikipedia.orghttp://en.wikipedia.org• Currier Glenn W. and Adam Trenton Currier Glenn W. and Adam Trenton

“Pharmacological Treatment of Psychotic “Pharmacological Treatment of Psychotic Agitation” Agitation” CNS DrugsCNS Drugs 2002. 2002.

Serretti Alessandro et al. “New Serretti Alessandro et al. “New Antipsychotics and Schizophrenia: A Antipsychotics and Schizophrenia: A

Review on Efficacy and Side Effects” Review on Efficacy and Side Effects” Current Medicinal Chemistry, 2004.Current Medicinal Chemistry, 2004.