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Pharmacotherapy With Anti

Psychotic Medications
Danesh A. Alam, M.D.
Fellow, Psychopharmacology and Research
Psychiatric Clinical Research Center
University of Illinois at Chicago

Rauwolfia Serpentina:
The First Herbal Antipsychotic
The first antipsychotic, Rauwolfia Serpentina, was
prescribed by physicians in ancient India over two
millennia ago.
The ancient Ayurvedic pharmacopoeia describes the use
of R. Serpentina in the treatment of insanity
(oonmaad in Sanskrit). onmaad is a description of
psychosis by the Ayurvedic physician Chakra (circa
1000 BC) as an abnormal condition of the mind,
wisdom, perception, knowledge, memory, character,
creativity, conduct, and behavior.

Rauwolfia Serpentina:
The First Herbal Antipsychotic
In 1931, Sen and Bose described the tranquilizing and
antihypertensive effects of R. Serpentina root extracts.
(Rauwolfia Serpentina: a new Indian drug for insanity and
high BP. Indian Medical World 1931:11:194-201).
In 1952, reserpine was isolated from Rauwolfia extracts.
Arvid Carlsson (Sweden) discovered the central nervous
system neurotransmitter properties of dopamine while
studying the mechanism of action of reserpine. Reserpine
works by depleting cells of dopamine, thus, reducing brain
dopaminergic activity.

Anti Psychotic Drugs


Chlorpromazine, 1952
Developed as an anti-autonomic agent
~20 anti-psychotic drugs available (US)
1st generation or typical i.e.chlorpromazine, haloperidol, fluphenazine
etc. vs. 2nd generation or atypical i.e.risperidone, olanzapine, quetiapine etc.

Antipsychotics
Common Indications
Schizophrenia
Schizoaffective
disorder
Mood Disorder with
psychosis
Dementia with
psychosis
Delirium
Delusional disorder
Psychosis secondary to
a non-psychiatric
medical disorder

Developmental

disability with
psychosis and/or
aggression
Tourettes disorder,
Huntingdons
chorea, intractable
hiccups
Acute Mania
Augmentation in
Major Depression
and Bipolar disorder

Schizophrenia: Symptom domains


Positive symptoms
Hallucinations
Delusions
Negative symptoms (deficit syndrome)
Primary
Secondary
Dysphoria
Neuroleptic-induced deficit syndrome (NIDS)
Cognitive symptoms
Dissociated thinking
Disorganization of thoughts
Attentional impairments

Antipsychotics: Mechanism of Action


Dopamine hypothesis
Increased release
Increased sensitivity of postsynaptic receptors
Dopamine receptor subtypes
Serotonin
Norepinephrine
Gamma-aminobutyric acid (GABA)
Glutamate
N-methyl-D-aspartate (NMDA)
Phencyclidine (PCP)
Peptides
Neurotensin
Cholecytoskin (CCK)
Somatostatin (SOM)

Dopamine Receptors
Plethora of DA receptors exist
5 pharmacological subtypes:
D1, D2, D3, D4 and D5
D2 Receptor: Most extensively studied
Stimulated by agonists for treatment of Parkinson's
Blocked by antagonists for treatment of Schizophrenia

Dopamine Pathways (4)


NIGROSTRIATAL DOPAMINE - projects from substantia nigra
to basal ganglia - controls movements
MESOLIMBIC DOPAMINE -projects from midbrain ventral
tegmental area to nucleus accumbens- delusions, hallucinations,
pleasurable sensations
MESOCORTICAL DOPAMINE -projects from midbrain ventral
tegmental area, sends axons to limbic cortex - mediates (+) and
(-) symptoms
TUBEROINFUNDIBULAR DOPAMINE -projects from
hypothalamus to anterior pituitary gland - controls prolactin
secretion

2nd Generation or Novel Antipsychotics


Clozapine (Clozaril)

Risperidone (Risperdal)

Olanzapine (Zyprexa)
Quetiapine (Seroquel)

Ziprasidone (Geodon)

2nd Generation/Novel/Atypical?
Profile
Diminished extrapyramidal side effects (EPS)
Minimized risk for tardive dyskinesia (TD)
No hyperprolactinemia
Beneficial for treatment of refractory patients
Improved negative symptoms
Improved cognitive/mood symptoms

The Role of Clozapine


Advantages

Disadvantages

Treatment of refractory patients

Agranulocytosis

Negative symptoms

Seizures

Minimal risk of EPS or TD (?)

Weight gain

No prolactin increase

Orthostasis
Tachycardia
Sedation

Sialorrhea
Constipation

Refractory Psychosis
Change anti-psychotic after adequate dosage
trial
Consider noncompliance and depot injections
Antipsychotic combinations
e.g., addition of neuroleptic
Adjunctive medications

Long-Acting (or Depot) Antipsychotics


Esters synthesized from the hydroxyl group of active
base and long-chain fatty acids
Dissolved in sesame oil vehicle
Ester is hydrolyzed by plasma esterases after
injection and slow release into systemic circulation
Css achieved in about 3 months
Terminal elimination half-life: 3 weeks

Depot Antipsychotics: Potential


Advantages
May benefit treatment-refractory patients on oral
preparations
May decrease noncompliance

Bioavailability approaches 100%


Lower and more predictable plasma drug levels with

clinically equivalent doses of oral preparations


Longer duration of action

Transition from Oral to Depot


Antipsychotics
Oral supplement during the vulnerable period
Use a high (or loading) depot dose initially

Increased frequency of injections early in


course of depot therapy

Antipsychotic Combinations I
Proposed Rationale:
Extensive unpublished clinical experience? (difficult
to examine without bias)
Differences in pharmacological action between
typicals and atypicals? (poor understanding of
required neurochemical action)

Extensive published evidence? (no controlled trials to


date. Most published studies examine addition of
typical to clozapine)

Antipsychotic Combinations II
Temporary Situations:
Lead-In combinations - typicals supposedly
having more rapid action during acute
emergency)
Top-Up combinations - addition of typical to
overcome acute exacerbation

Switch-Over combinations - when switching


between antipsychotics

Adjunctive Treatment
Anticholinergics

Benzodiazepines (anxiety, akasthisia)


Carbamazepine (effective in acute episode; long

term studies not done)


Lithium (excitement, overactivity, euphoria)

Valproic acid (psychosis?)


Propranolol (akasthisia, psychosis)

Adverse Effects of Antipsychotics


Major Points
Atypical antipsychotics represent a significant departure
from the conventional neuroleptics
These agents can also adversely affect several systems

The most critical to consider are the neurological,


hematological, cardiovascular, and endocrine
Other problems occur due to their cholinergic or sexual
adverse effects
Drug interactions can also occur

Adverse Effects of Antipsychotics


Neurological
Acute EPS

Dose-related EPS
Primary vs. secondary negative symptoms
Neuroleptic malignant syndrome
Tardive dyskinesia (other tardive syndromes)

Seizures (e.g., clozapine)


Sedation, headache, withdrawal syndrome

Adverse Effects of Antipsychotics


Low EPS Risk of Atypical Antipsychotics
Preferential DA blockade in meso-cortico-limbic pathway
5HT2 5HT1c, or 5HT3 blockade
High 5HT2/DA2 blockade ratio
Low D2 occupancy
Rapid release of bound antipsychotic from receptor due to
loose binding (clozapine and quetiapine)
Anticholinergic effects
Antihistaminergic effects

Adverse Effects of Antipsychotics


Acute EPS
Maximum

NEUROLEPTICS

Minimum

RISPERIDONE

OLANZAPINE

(DOSE-RELATED

CLOZAPINE
ZIPRASIDONE
QUETIAPINE

Adverse Effects of Antipsychotics


Hematological
Neuroleptics
Clozapine-induced agranulocytosis

Management
Stop agent
Reverse isolation; supportive measures
GCSF (cytokines, filgastrim)

Rechallenging strategies

Adverse Effects of Antipsychotics


Cardiovascular
Related to both alpha adrenergic and muscarinic
effects

Hypotension
Tachycardia
Arrhythmogenic potential possible with all
antipsychotics

QTC interval

QTC prolongation
QTC dispersion
Torsade de Pointes

Adverse Effects of Antipsychotics


Anticholinergic
Most common with:
Clozapine
Olanzapine
Quetiapine
Low-potency neuroleptics

Adverse Effects of Antipsychotics


Neuroendocrine
Inconsistent effects on hormone-related activity

Pituitary (prolactin, menstrual dysfunction)


Thyroid

Antagonism of DA receptors in the pituitary can


result in increased prolactin levels, possibly causing:

Lactation/breast engorgement
Gynecomastia
Sexual dysfunction (decrease in sexual interest reversed
by bromocriptine)?
Anxiety and mood disturbance?

Adverse Effects of Antipsychotics


Sexual Adverse Effects
anti-Serotonin (5HT2)
anti-dopamine (impaired erection, inhibited orgasms)
anti-norepinephrine (reduced intensity of orgasm)
anti-cholinergic (impaired erection)
anti-histamine (loss of libido, impaired erection)

Adverse Effects of Antipsychotics


Sexual Adverse Effects: Management
Dosage reduction, avoidance of
antimuscarinic agents
Switching to another agent
Various drugs may be helpful
(e.g., sildenafil, yohimbine (NE),
cyproheptadine (5HT2 antagonist )

Adverse Effects of Antipsychotics


Weight Gain: General Issues
Recognized problem since chlorpromazine

More common with atypicals


Altered metabolism vs. satiety vs. activity

Diabetes mellitus associated with typicals and


atypicals

More problems managing DM


New-onset cases of DM;
Ketoacidosis

Long-term weight-associated concerns


Elevated triglycerides and cholesterol
Heart disease and hypertension

Adverse Effects of Antipsychotics


Mean weight gain after 10 weeks (kgs)
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Allison DB et al. Am.J.Psychiat;156;1686-1696, 1999

Adverse Effects of Antipsychotics


Weight Gain: Mechanism
Increased calorie consumption
Decreased calorie use (less activity, sedation)
Mechanism of weight gain is unknown
Genetic contribution
Dopamine blockade (e.g. amantadine)
Noradrenergic blockade (e.g., amphetamines)
Serotonin blockade (e.g., fenfluramine;
5HT2c, 2a, 1a )
Histamine blockade (e.g., antihistamines)
Glucose and insulin dysregulation

Adverse Effects of Antipsychotics


Weight Gain: Treatment Options
Dietary changes

Patient education about causes


Strategies to reduce food intake
Exercise

Screening for related health problems

Diabetes
Hypertension
Serum cholesterol

Adverse Effects of Antipsychotics


Ocular

Retinitis pigmentosa (e.g., thioridazine)


Cataracts (e.g., quetiapine?)

Adverse Effects of Antipsychotics


Ocular Assessments in Quetiapine Trials
Cataracts in chronic dog studies
No cataracts seen in two 1-year monkey studies
Lens changes in a long-term clinical trial were comparable

to control group (haloperidol)


Across all controlled clinical trials, the proportions of
patients with lens changes were similar in quetiapine,
haloperidol , and placebo groups
Periodic ocular examinations are recommended

Summary of Antipsychotic Treatment


Fewer adverse effects with atypicals
greatly reduces adverse effects burden
clozapine is an exception
Major decrease in risk of EPS and TD
Prolactin increase and other risks are lower
Weight gain is a problem
varies across atypical class

Trivia
Antipsychotic that cause less weight gain: molindone
& ziprasidone
droperidol- only approved for IV use in anaesthesia
Pimozide approved for use in Tourettes only
Clozapine- reduces suicide in schizophrenia
All antipsychotics lower the seizure threshold, 2nd
generation <1%
Other meds that cause ac. Dystonia, akathesia,
parkinsonian sideeffects and NMS- prochorperazine
(compazine), metoclopramide, promethazine
(Phenergan).