Antipsychotic Drugs

Learning Objectives
• 1. Describe the dopamine hypothesis of schizophrenia
• 2. List the major receptors blocked by anti-psychotic drugs.
• 3. Describe the pharmacodynamics of older anti-psychotic
drugs and relate these characteristics to their clinical use.
• 4. Identify the main characteristics and clinical uses of newer
atypical anti-psychotic drugs.
• 5. List the major adverse effects of the anti-psychotic drugs.
 Introduction to Psychiatric
Disorders
Neurosis Psychosis

Less serious psychiatric More serious disorder

disorder

No change in personality Change in personality

Has insight and no loss of No insight and loss of

contact with reality contact from reality
Neurosis
 Schizophrenia

Emil Kraepelin “Dementia Praecox’ (1896)

Blueler “Schizophrenia”
Onset: adolescence or young adulthood
 High number years of productive life lost.

 50% of all inpatient psychiatry beds

 $50 billion annual cost to US.

 Schizophrenia
• It’s a psychosis
• Characterized by withdrawal from reality,
• Illogical patterns of thinking, delusions, and hallucinations
• Accompanied in varying degrees by other emotional,
behavioral, or intellectual disturbances.
 Subtypes
• DSM-IV Subtypes - hierarchy in the order of consideration
• Catatonic
• Disorganized (previously called hebephrenic)
• Paranoid
• Undifferentiated - not above, but Criterion A still met
• Residual - Criterion A not currently met
• Simple
• Other types.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).
American Psychiatric Press; 1994 ISBN: 0890420629
 Neuropathology
• Genetic
Neurodevelopmental hypothesis
Neurodegenerative hypothesis
• Dopamine hypothesis
• Glutamatergic hypothesis
Ventricular enlargement in monozygotic
twin with schizophrenia

Barondes, 1993
Rapid loss of brain volume during
adolescence in Schizophrenics

Thompson et al, 2001

Dopamine theory
 SERATONIN THEORY

• Atypical antipsychotics have not much activity on

Dopamine receptors

• LSD central 5HT agonist produces hallucinations

and sensory disturbances seen in psychosis

• 5 HT has role in negative symptoms

So there is a role for 5 HT Also in schizophrenia
 Glutamate theory
• Glutamate + NMDA antagonists such as:

• Phencyclidine + Ketamine  psychotic symptoms.

• Reduced glutamate receptor density in the post mortem brains of

schizophrenics.
Mechanism of action of
antipsychotics
• Antagonism of D2 in mesolimbic pathway
produces relief of positive symptoms.

• No differentiation between different regions.

• Motor symptoms due to antagonism in
nigrostriatal pathway.
• Enhance prolactin secretion (tuberoinfundibular
pathway).

• Reduce pleasure.

• Worsen negative symptoms ( blockade of D2

receptors in prefrontal cortex)
• Atypical Drugs are used for Negative forms
 Serotonin receptors

• 5HT2A receptors are most important.

• 5HT2A activation = Neuronal inhibition.
• 5HT2a Antagonists increase release of Dopamine
ONLY at Nigrostriatal pathway.
• No Parkinsonism-Like Symptoms
• No Extrapyramidal Symptoms
• In contrast in Mesolimbic system:
• combined effects of Dopamine + Serotonin
antagonism counteracts the increased dopamine
function which give rise to positive symptoms.

• Further, enhancing dopamine may also improve

the negative symptoms.
 TYPICAL NEUROLEPTICS

• Typical neuroleptics are EFFECTIVE antipsychotic agents

• Typical Side Effects:
• Extrapyramidal motor system

• Typical neuroleptics
• block the dopamine-2 receptor.
 TYPICAL NEUROLEPTICS

• Typical neuroleptics:

• DO NOT PRODUCE  General Depression of the CNS

• Respiratory depression

• DO NOT DEVELOP

• Abuse, addiction, physical dependence

• Blocking D2 Receptors which is Reward/Pleasure

 TYPICAL NEUROLEPTICS

• Typical neuroleptics are generally more effective against

positive (active) symptoms of schizophrenia than the
negative (passive) symptoms.
 ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
• Anticholinergic (antimuscarinic) side effects:
• Dry mouth, blurred vision, tachycardia, constipation, urinary
retention, impotence
 ADVERSE EFFECTS OF
TYPICAL NEUROLEPTICS
• Antiadrenergic (Alpha-1 Blockade) side effects:
• Orthostatic hypotension w/ reflex tachycardia
• Sedation
 ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
• Antihistamine effect:
• Sedation
• Weight gain
 KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS
(EPS).

• DYSTONIA
• NEUROLEPTIC MALIGNANT SYNDROME
• PARKINSONISM
• TARDIVE DYSKINESIA
• AKATHISIA
TONIC D2 Antagonism
Endocrinal adverse effects
• Weight gain

• common, antihistamine effect

• Photosensitivity (v. common w/ phenothiazines)

• Type 4 Hypersensitivity Cell Mediated

• Lowered seizure threshold (common with all)

• Leucopenia , Agranulocytosis

• RARE w/ phenothiazines

• Infections  Sepsis  Death

• Retinal pigmentopathy

• RARE w/ phenothiazines
 Atypical antipsychotics
• Unique affinity for specific receptors
• Both positive and negative symptoms
• Refractory to classical drugs
• LESS Extra pyramidal symptoms
 Clozapine

• Very weak D2 blocking action.

• Few or no extrapyramidal symptoms.
• Relatively selective = D4 and 5HT receptors.
• Metabolized = CYP3A4
• Major limitation is higher incidence of Agranulocytosis.
• Epileptogenic .
• Precipitation of diabetes
• Weight gain.
• Myocarditis.
• Reserve drug in resistant schizophrenia.
 Risperidone

• Similar to Clozapine
• MORE POTENT D2 BLOCKER.
• Extra Pyramidal Symptoms + Increased Prolactin
• CAUTION: for Increased risk of STROKE in ELDERLY.
 Aripiprazole
• Atypical Antipsychotic
• PARTIAL AGONIST = D2 + 5HT1A receptors.
• EFFICACIOUS

• ANTAGONIST = 5HT2 receptors

• Symptoms:
• EPS, Hyperprolactinemia, Hypotension + Q-T prolongation
• NOT SIGNIFICANT
• MINIMAL EFFECTS

• Metabolized = CYP3A4 + CYP2D6

 Adverse effects of Atypical
Antipsychotics

• Adverse metabolic effects

 Two fold increase = Type 2 DM
 Two fold increase = CV mortality
 Significant increase in triglyceride levels.
 Weight gain.
 Other adverse effects
• Arrythmias
• QT prolongation = Aripiprazole
• Sudden cardiac deaths = Risperidone
• Epileptogenesis
• Agranulocytosis = Clonidine
• Cataract formation = Quetiapine
 Choice of an antipsychotic

• Needs long term treatment

• The choice is basically by avoidance of adverse effects

and prior history of patient response.

• Whether typical or atypical it is debatable.

• Atypical antipsychotics have less neurological side effects.

• But the metabolic derangements and cardiovascular
risks significant.

• Olanzapine and clozapine  highest incidence.

• Initially started with more metabolically inert agents
like ziprasidone and aripiprazole.

• If failure, clozapine = last resort.

• Many reasons for relapse or inadequate response
 ongoing substance use

 psychosocial stressors

 inherent refractory illness

 poor medication adherence

• Serum drug levels not a good guide.
• Long acting injectables can be tried in case of
medication nonadherence.

• Risperidone + Paliperidone are available

• Aripiprazole + Olanzapine under development.
• Refractory schizophrenia:
• is defined using the Kane criteria

• Failed 6-week trials of two separate agents and a

third trial of a high-dose typical antipsychotic
agent (e.g., haloperidol or fluphenazine 20
mg/day).
• Response rates to typical antipsychotic agents 20%
reduction in the standard rating scales.

• And Atypicals except clozapine 10%.

• Clozapine trial needs 6 months.
• Response rate is consistently 60% in refractory
schizophrenic patients.
 Psychosocial

• Supportive therapy
• This is well SUPPORTED as an ADJUNCT to medication.

• (INSIGHT ORIENTED approaches are CONTRAINDICATED.)

• Social skills training

• This especially focuses on amelioration of negative symptoms by means
of cognitive-behavioral methods.
 Indications for ECT
• Catatonic stupor

• If person refuses to breath

• Uncontrolled catatonic excitement

• Acute exacerbation NOT controlled with drugs

• IM Haloperidol

• Severe side effects with drugs.

• Electroconvulsive Therapy (Monotherapy)

• Very rarely

• Psychosurgery limbic leucotomy

• Removes emotions, desires, cravings  INHUMANE  SUICIDE

 Other indications of antipsychotics
• Anxiety disorder
• Huntington's disease
• Chorea, INVOLUNTARY
• D2 Antagonist to treat Chorea
• HIGH Dopamine in Nigrostriatal Pathway
• Tourette's syndrome
• Facial ticks, obscenities
• D2 Antagonism to treat
• HIGH Dopamine in Nigrostriatal Pathway
• Autism
• Headbanging
• D2 Antagonism to treat
• High Dopamine in Nigrostriatal Pathway
• Antiemetic
• Metoclopramide
• Domperidone
• D2 Antagonism in
• Prevent vomiting CTZ + Vomit Center in Area Postrema
• Hiccups
• Could last for decades
• High Dopamine in Nigrostriatal Pathway
• Incoordinate movement of Diaphragm