Antipsychotic Drugs:

Treatment of Psychosis and Mania

KEYWORDS:
affective disorder-psychotic; anticonvulsants; antidepressant agents; antipsychotic
agents; bipolar disorder; lithium; psychopharmacology
ABSTRACT:

This lecture deals primarily on the PK/PD of

pharmacologic preparations used in the management of
diseases with manifestations of Psychoses and Mania;
in relation to the pathophysiology of these Diseases.

The introduction of modern trends in psychopharmacology,

has revolutionized the treatment of major mental disorders,
with manifestations of psychoses and mania including
Schizophrenia.
LEARNING OBJECTIVES:

1. Define Psychosis.
2. Describe the common Psychotic disorders.
3. Discuss briefly Schizophrenia as a prototypical
disorder for the impact of antipsychotic therapy.
4. Describe the Positive and Negative symptoms of
Schizophrenia and discuss the pathophysiology
of these symptoms.
LEARNING OBJECTIVES:

5. Discuss the dopamine (DA) over-activity Hypothesis.

6. Discuss the PK/PD of Drugs used in the pharmacologic
management of diseases with manifestations
of Psychosis and Mania.
7. Compare Alogia and Avolition. Describe how the two
manifestations come about in patients manifesting
Psychosis and Mania.
Psychosis:
 is a symptom of mental illnesses.

 Characterized by:
a) a distorted sense of reality, or
b) non-existent sense of reality.

= Psychotic Disorders have varied etiologies;

 each demanding a unique treatment approach.
Common Psychotic Disorders:

1) Mood disorders with psychotic features

(major depression or mania)
2) Substance-induced psychosis
3) Dementia with psychotic features
4) Delirium with psychotic features
5) Brief psychotic disorder
6) Delusional disorder
7) Schizoaffective disorder
8) Schizophrenia
Schizophrenia:

= a worldwide prevalence  of 1%

= Schizophrenia considered as the prototypic disorder,

both for:

1) understanding psychosis,

2) the impact of Antipsychotic therapy.

 Signs and Symptoms of Schizophrenia:
1. Positive symptoms:
 identified as superimposed behaviors.
a) Hallucinations
b) Delusions
c) Disorganized speech
d) Disorganized or agitated behavior
e) Chronic jerking

2. Negative symptoms:
 absence of normal function, like loss of sensation.
a) Apathy (feeling of drained energy)
                      b) Alogia 
                      c) Avolition 
d) Cognitive deficits
What is Avolition in Psychology?

The lack of interest or engagement in

goal-directed behavior.

Apathy, feeling of being drained of energy and

of interest even in the usual goals or ADL.

The loss of motivation; the will or desire to participate

in productive activities or even to do his ADL.
Eugen Bleuler described Avolition in his mnemonic
known as Bleuler's four A's:

Avolition
 a disturbance of: Affect, Association,
Ambivalence and Autism.

Alogia:
 the struggle to give even brief answers to questions.

Anhedonia:
 a diminished capacity to experience pleasant emotions.
a difficulty in experiencing interest or pleasure.
Cognitive Deficits (negative symptom)
like deficits in:

a) Working memory

b) Processing speed

c) Social cognition

d) Problem solving
 (test 1.5 to 2 standard deviations
below norms of population).
Cognitive Dysfunction:
 the strongest predictor of functional
impairment among schizophrenia patients.

Negative Symptoms and Cognitive Deficits:

 have limited improvement with

antipsychotic treatment.
The Dopamine theory of Psychosis,

 was reinforced by the high risk for drug-induced

psychosis among patients/ individuals taking
substances,

 that directly increased synaptic dopamine availability,

like:
a) Cocaine
b) Amphetamines
c) L-dopa for the treatment of Parkinson's disease
The Dopamine Hypothesis of Psychosis:

 is based on the therapeutic efficacy of Chlorpromazine

in the pharmacologic management of Schizophrenia,
as elucidated by Carlson.

 stated that postsynaptic DA, D2 receptor antagonism

was the common mechanism that explained its
antipsychotic properties.
Limitations of the DA hypothesis:

a) It does not account for the cognitive

deficits associated with schizophrenia
that appear to be related to decreased
DA signaling. (in the prefrontal cortex)

b) It does not explain the psychotomimetic

effects of agonists of other pathways like:
1) d-lysergic acid  a potent serotonin
5-HT2 receptor agonist.

2) effects of phencyclidine and ketamine

 antagonists to the glutamate receptor,
N-methyl-D-aspartate (NMDA).
Reserpine, (from Rauwolfia)
 exhibited antipsychotic properties,

 by decreasing dopaminergic neurotransmission

through the depletion of monoamines from
the presynaptic nerve terminals.

 and not a D2 receptor antagonists.

The dopamine (DA) over-activity hypothesis has led
to the development of the first therapeutic class of
antipsychotic agents;

 the typical or first-generation Antipsychotic drugs.

Typical or First-generation Antipsychotic Drugs:

= MOA:
 significant DA , D2 receptor antagonist (blockade)

= Significant side effects:

 associated risk for extrapyramidal side effects.
= In searching for non-dopaminergic alternative approaches
for the management of psychosis;

= on top of the experience with the use of the

typical Antipsychotic drugs, like Clozapine,

 the result was an Atypical clinical profiling of

Antipsychotic efficacy;
 with limited extrapyramidal side effects.

= These endeavor has lead to the use of newer

Antipsychotic agents up to the present.
The general MOA of newer Antipsychotics:

 potently antagonize the 5-HT2 receptor, and

 less potently block D2 receptors than the older

typical antipsychotic agents,

 these result in the atypical clinical profile of

Antipsychotic drug efficacy with,

 limited extrapyramidal side effects.

Other medications in the horizon:
a) target the glutamate and 5-HT7 receptor subtypes.

b) target receptors for γ-aminobutyric acid (GABA)

c) target acetylcholine receptors.

(both muscarinic and nicotinic)

d) target even peptide hormone receptors (like oxytocin)

Pathophysiology of Psychosis:

Common Etiology of Psychosis:

 is the excessive dopaminergic neurotransmission
in the mesolimbic dopamine pathways.

= Not all Psychosis is Schizophrenia,

and effective schizophrenia treatment may not be applicable
to other psychotic disorders.

= The effectiveness of dopamine receptor (D2) antagonists,

 for the positive symptoms of Psychosis as manifested
in most psychotic disorders;
 suggests a common etiology for these symptoms.
> In the Substance-induced Psychotic Disorders:
 the Substance may:

1) Directly increase postsynaptic DA activity

through increased presynaptic
neurotransmitter release.  (Amphetamine)

2) Inhibition of presynaptic DA reuptake

(Methylphenidate, Cocaine, and Amphetamine)

3) Increased DA availability.  (L-dopa)

> NMDA Antagonists __ Phencyclidine and Ketamine:

 indirectly stimulate DA availability;

 by decreasing the glutamate-mediated

tonic inhibition of DA release in the
mesolimbic DA pathway.
Psychoses related to Delirium and Dementia:

 in particular the Dementia of the Alzheimer Type,

that share a common etiology:

 the deficiency in Cholinergic neurotransmission,

either due to:
a) the anti-cholinergic properties of medications,
b) age-related, or
c) disease-related neuronal loss,
d) or all of item a, b and c.
= Studies show that among hospitalized elderly patients,
increased plasma concentrations of
Anticholinergic medications;
 are directly associated with increased delirium risk.
(Flacker and Lipsitz, 1999);

= Unlike in Alzheimer's Dementia, where the

psychotic symptoms;
 are directly related to Cholinergic neuronal loss,
 and may respond to Acetylcholinesterase therapy,

Delirium may have other causes besides the medication-related

anticholinergic issues, which require specific treatment;
 in addition to removal of offending anticholinergic
medications.
 Delirium may have other causes besides the,
medication-related anticholinergic drug issues,
which require specific treatment;
 in addition to removal of offending anticholinergic
medications.

Causes of Delirium other than the Medication-related

Anticholinergic Properties:
1) Infections
2) Electrolyte imbalance
3) Metabolic derangement like:
a) Very high fever
b) Metabolic acidosis or alkalosis
Mania:
 is characterized by:
1) periods of elevated, expansive or irritable mood.
2) with co-existing manifestations of increased energy.
3) goal-directed activity.
4) decreased need for sleep.
Mania represents one pole, of what had been termed:

= Manic-depressive Illness, referred to as

 Bipolar Disorder.

Like Psychosis:
 Mania may be induced by medications, like:
a) DA agonists
b) Antidepressants
c) Stimulants
d) Substances of abuse, primarily,
1) Cocaine

2) Amphetamines
Generalities:

= All Atypical Antipsychotic Agents;

 with the exception of Clozapine and Iloperidone

 have indications for Acute Mania.

= The Typical Antipsychotic Drugs:

 are also effective in Acute Mania,

 but often have higher risk for extrapyramidal

symptoms (EPS).
Clinical response to Indicated Pharmacologic Drugs:
 usually occur within 7 days of medication.

a) decreased psychomotor agitation and irritability

b) increased sleep
c) reduced or absent delusions and hallucinations

= Patients with Mania need continuous Antipsychotic treatment

for months even after the resolution of psychotic and
manic symptoms,

 in combination with a mood stabilizer; like:

a) Lithium, or
b) Valproic acid preparations (Divalproex)
Short-Term Treatment Delirium and Dementia:
= Psychotic symptoms of Delirium or Dementia,
 are treated with low doses of medications.

= May have to repeat dosage at frequent intervals

initially to achieve adequate behavioral control.

= Not a single Antipsychotic Drug has received approval,

 for dementia-related Psychosis.

= All Antipsychotic Drugs carry warnings that

they may increase mortality in this setting.

= The Anticholinergic effects of drugs,

may worsen Delirium and Dementia.
Common Side Effects of Anti-psychotic Drugs:

a) weight gain
b) hyperlipidemia
c) hyperglycemia
Drugs of choice in Delirium and Dementia:
1) High-potency Typical Antipsychotic Drugs
(Haloperidol)
2) Atypical Antipsychotic Agents with limited
anti-muscarinic properties
(Risperidone)

= The best-tolerated doses in dementia patients:

 ¼ of the adult Schizophrenia doses.

( Risperidone = 0.5 to 1.5 mg/day)

= Side effects:
 Extrapyramidal neurological symptoms (EPS):
1) Orthostasis 2) Sedation
= Significant antipsychotic benefits are usually seen;

 in Acute Psychosis within 60-120 minutes

after the drug administration.

= Delirious or demented patients may be

reluctant or unable to swallow tablets,

 so, oral dissolving tablet (ODT) preparations

of Risperidone, Aripiprazole, and Olanzapine;

 or, the liquid concentrate forms of Risperidone or

Aripiprazole, are options.
= The oral dissolving tablets, adhere to any moist
tongue or oral surface, cannot be spit out,
and are then swallowed along with oral secretions.

= Intramuscular (IM) administration of

Ziprasidone, Aripiprazole, or Olanzapine

 are option for unconscious patients.

 Major Depression:
> Major Depressive Disorder with Psychotic Features
 require lower doses of Antipsychotic drugs,
given in combination with an antidepressant.

> In Mood Disorder patients are more susceptible to EPS

and other adverse drug events
specially for the "drug-naïve“ patients.

Pathophysiology of Major Depression:

 decreased noradrenergic tone in projections of the
locus coeruleus to the PFC and Limbic areas.
= Almost all atypical antipsychotic medications;
 are potent 5-HT2A antagonists,

 with 5-HT2A receptor occupancies

exceeding 80% at modest dosages.

= Both 5-HT2A and 5-HT2C receptors are G-protein coupled.

= Upon stimulation, result in;

 increased production of intracellular inositol
trisphosphate (IP3).

> Atypical Anti-psychotics:

 are actually inverse agonist to 5-HT2A and 5-HT2C receptors,
and the MOA is antagonism
 facilitates DA release, and
Atypical Anti-psychotics:
 are actually inverse agonist to
5-HT2A and 5-HT2C receptors,
 the MOA is Antagonism.

 facilitates DA release,
 and increases noradrenergic outflow
from the locus coeruleus.
Schizophrenia:

Immediate goals of Acute Antipsychotic Therapy

in Schizophrenia:

1) Reduction of agitated, disorganized, or hostile behavior.

2) Decrease the impact of hallucinations.
3) Improvement of organization of the thought processes.
4) Reduction of social withdrawal.

The preferred Antipsychotic agents for Schizophrenia:

 attributed to the results of improved neurological risk profile.

 the use of non-sedating Antipsychotic agents,

plus low doses of Benzodiazepines.
Important Considerations:
A. Schizophrenia patients have:
 A 2-fold higher prevalence of:
a) Metabolic syndrome
b) Type 2 diabetes mellitus.

B. Cardio-metabolic risk assessment profile is a must

in the onset of management of Schizophrenia.
 A 2-fold greater cardiovascular related
mortality rates than the general population.
ADA recommendation of baseline determination of:
1) Weight 4) Serum glucose
2) BP 5) Serum lipids
3) Waist circumference 6) Good family history
(hip to waist ratio) and Genogram

C. Drug-induced Parkinsonism;
 can occur especially among elderly patients
under antipsychotic agents with high D2 affinity.
Mechanism of Action of Antipsychotics:
 reduction in dopaminergic neurotransmission
which is achieved through:
1) D2 antagonism
or
2) Partial D2 agonism ( Aripiprazole)

Aripiprazole:
= has affinity for D2 receptors slightly less than DA itself,
= but, its intrinsic activity is ~25% that of DA.
Aripiprazole has the capacity:

a) To stimulate D2 receptors in the brain areas

where synaptic DA levels are limited;

b) or, decrease dopaminergic activity when

Dopamine concentrations are high
(in the mesolimbic cortex)

 is the basis for the clinical effects of

Aripiprazole in Schizophrenia.
D3 and D4 Receptors in the BG and Limbic System:

= The discovery that D3 and D4 receptors,

 preferentially expressed in the limbic areas,

 has led to identify selective inhibitors for

these receptors that might have
antipsychotic efficacy and low EPS risk.
Tolerance and Physical Dependence to Antipsychotics:
= Antipsychotic drugs are not addicting,
= but, tolerance to the antihistaminic and anticholinergic
effects of antipsychotic agents;
 usually develops over days or weeks.

= Tolerance at striatal dopaminergic systems,

 is due to the development of receptor supersensitivity
(upregulation of supersensitive DA receptors)
 referred to as D2High receptors
 explains the emergence of withdrawal-emergent
dyskinesias which contribute to the
pathophysiology of tardive dyskinesia.
= Tolerance at the striatal dopaminergic systems
 is due to the development of
Receptor Super-sensitivity.

 mediated by up-regulation of the

supersensitive DA receptors

 referred to as D2High receptors.

 leading to the emergence of a phenomenon

of withdrawal-emergent dyskinesia.

 which contribute to the pathophysiology of

tardive dyskinesia.
Pharmacokinetics:
= Most antipsychotic drugs are highly lipophilic.

= Highly membrane- or protein-bound,

= Accumulate in the brain, lung, and other tissues
with a rich blood supply.

= Enter the fetal circulation and breast milk.

= Short half-lives, but biological effects of a single dose of most

antipsychotic medications usually persist for at least 24 hours.
Pharmacokinetics:

= Elimination from the plasma is more rapid than from sites

of high lipid content and binding, like the CNS.
 Half-lives in the CNS exceed those in plasma.

= Metabolites of long acting injectable medications

 were detected in the urine several months after
drug administration was withdrawn.
Huntington's Disease:
 a neuropsychiatric condition, which like tic disorders,
is associated with basal ganglia pathology.

= DA blockade can suppress the severity of

choreoathetotic movements,
 but the risks associated of excessive DA
antagonism outweigh the marginal benefit.

= Inhibition of the vesicular monoamine

transporter type 2 (VMAT2)
= with Tetrabenazine replaced DA receptor blockade
 in the management of chorea.
Autism:

= a disease (neuropathology is incompletely understood),

associated with:
1) Explosive behavioral outbursts
2) Aggressive or self-injurious behaviors
that may be stereotypical.

= Risperidone: has FDA approval for irritability

associated with Autism in children and
adolescent patients ages 5-16.

= is also use for disruptive behavior problems

in Autism and other forms of Mental retardation.
Anti-Emetic Use of Antipsychotic Drugs:

= Most Antipsychotic Drugs protect against,

 the nausea-and emesis-inducing effects of;

DA agonists acting at central DA receptors

at the Chemoreceptor Trigger Zone (CTZ)
of the medulla.

= Antipsychotic drugs are effective anti-emetics

even at low doses.
= Antipsychotic drugs do not antagonize drugs or
other stimuli that cause emesis by an action on:
a) the nodose ganglion
b) or, locally on the GI tract

= Potent Piperazines and Butyrophenones;

 are effective against nausea secondary
to vestibular stimulation.

= Commonly used anti-emetic Phenothiazines,

 are weak DA antagonists.
Antipsychotic Use in Pregnancy and Lactation:

= Antipsychotic agents;
 carry pregnancy class B or C warnings.

= Haloperidol has the best safety profile,

 but newer Antipsychotic drugs,
like Risperidone, are now used.

= Since Antipsychotic drugs;

 are designed to cross the blood-brain barrier,
 they also have high rates of placental passage.
= Estimated placental passage ratios:

a) Olanzapine  highest at (72%)

b) Haloperidol  (42%)

c) Risperidone  (49%)

d) Quetiapine  (24%)
= Neonates exposed to Olanzapine;
 has a tendency towards greater neonatal
intensive care unit admission.

= The significant risk for Antipsychotic drug

toxicity when used during lactation is due to:

 the low level of infant hepatic catabolic activity

in the first 2 months of life.
 the inability of newborns to adequately
metabolize xenobiotic.