DRUG TREATMENT OF PSYCHOSIS

Psychosis

Psychosis is a thought disorder characterized by disturbances of reality and perception, impaired cognitive functioning, and inappropriate or diminished affect (mood).

Psychosis denotes many mental disorders.

Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a

marked thinking disturbance.

Psychosis-Producing Drugs

1) Levodopa2) CNS stimulants

a) Cocaine b) Amphetaminesc) Khat, cathinone, methcathinone

3) Apomorphine 4) Phencyclidine

Schizophrenia

• Pathogenesis is unknown.• Onset of schizophrenia is in the late teens -

early ‘20s.• Genetic predisposition -- Familial incidence. • Multiple genes are involved.• Afflicts 1% of the population worldwide.• May or may not be present with anatomical

changes.

Schizophrenia• A thought disorder.

• The disorder is characterized by a divorcement from reality in the mind of the person (psychosis).

• It may involve visual and auditory hallucinations, delusions, intense suspicion, feelings of persecution or control by external forces (paranoia), depersonalization, and there is attachment of excessive personal significance to daily events, called “ideas of reference”.

Schizophrenia

Positive Symptoms. Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms. Apathy, social withdrawal, anhedonia, emotional blunting,

cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.

These symptoms are progressive and non-responsive to medication.

Etiology of Schizophrenia

Idiopathic

Biological Correlates1) Genetic Factors2) Neurodevelopmental abnormalities.3) Environmental stressors.

Etiology of Schizophrenia

Characterized by several structural and functional abnormalities in the brains of schizophrenic patients:

1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia.

Dopamine Theory of Schizophrenia

Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.

There is a greater occupancy of D2 receptors by dopamine => greater dopaminergic stimulation

Dopamine Theory of Schizophrenia

Dopamine Correlates:• Antipsychotics reduce dopamine synaptic activity.• These drugs produce Parkinson-like symptoms.• Drugs that increase DA in the limbic system cause

psychosis.• Drugs that reduce DA in the limbic system

(postsynaptic D2 antagonists) reduce psychosis.• Increased DA receptor density (Post-mortem, PET).• Changes in amount of homovanillic acid (HVA), a DA

metabolite, in plasma, urine, and CSF.

Pharmacodynamics

Anatomic Correlates of Schizophrenia...

Areas Associated with Mood and Thought Processes:

Frontal cortex

Amygdala

Hippocampus

Nucleus accumbens

Limbic Cortex

Dopamine Theory of Schizophrenia

Evidence against the Theory?• Antipsychotics are only partially effective in most

(70%) and ineffective for some patients.• Phencyclidine, an NMDA receptor antagonist,

produces more schizophrenia-like symptoms in non-schizophrenic subjects than DA agonists.

• Atypical antipsychotics have low affinity for D2 receptors.

• Focus is broader now and research is geared to produce drugs with less extrapyramidal effects.

Dopamine System

There are four major pathways for the dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.II. The Mesolimbic Pathway.III. The Mesocortical Pathway.IV. The Tuberoinfundibular Pathway.

THE DOPAMINERGIC SYSTEM

Catecholamines

Tyrosine Tyrosine hydroxylase

L-Dopa Dopa decarboxylase

Dopamine (DA) Dopamine hydroxylase

Norepinephrine (NE)(Noradrenaline) Phenylethanolamine-

-N-methyltransferase

Epinephrine (EPI)(Adrenaline)

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

Dopamine System• DOPAMINE RECEPTORS– There are at least 5 subtypes of receptors:– D1 and D5: mostly involved in postsynaptic

inhibition.– D2, D3, and D4: involved in both pre-and

postsynaptic inhibition.D2: the predominant subtype in the brain:

regulates mood, emotional stability in the limbic system and movement control in the basal ganglia.

Dopamine Reuptake System

Antipsychotic treatments

SCHIZOPHRENIA IS FOR LIFE

There is no remission

Antipsychotic treatmentsSchizophrenia has been around perhaps, since the

beginning of humankind, however, it was not until the last century that it was established as a separate entity amongst other mental disorders.

Many treatments have been devised:

Hydrotherapy: “The pouring of cold water in a stream, from a height of at least four feet onto the forehead, is one of the most certain means of subsiding violent, maniacal excitement that we have ever seen tried”... wrote an anonymous physician in the early 1800’s.

Antipsychotic treatments Lobotomies (Egaz Moniz).

In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.

In 1955, chlorpromazine was developed as an antihistaminic agent by Rhône-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.

Antipsychotics treatmentAntipsychotics/Neuroleptics

• Antipsychotics are the drugs currently used in the prevention of psychosis.

• They have also been termed neuroleptics, because they suppress motor activity and emotionality.

** These drugs are not a cure **• Schizophrenics must be treated with

medications indefinitely, in as much as the disease in lifelong and it is preferable to prevent the psychotic episodes than to treat them.

Antipsychotics/Neuroleptics

Although the antipsychotic/neuroleptics are drugs used mainly in the treatment of schizophrenia, they are also used in the treatment of other psychoses associated with depression and manic-depressive illness, and psychosis associated with Alzheimer’s disease. These conditions are life-long and disabling.

Antipsychotics/Neuroleptics

NON-compliance is the major reason for relapse.

Antipsychotic/Neuroleptics

Three major groups :1) Phenothiazines2) Thioxanthines

3) Butyrophenones

OLDER DRUGS

Antipsychotics/Neuroleptics

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

• Old antiphsychotics /neuroleptics are D2 dopamine receptor antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.

dopamine

receptor

antagonist

D2

Antipsychotics/Neuroleptics

• It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.

• The affinities of most older “classical” agents for the D2 receptors correlate with their clinical potencies as antipsychotics.

Antipsychotic/Neuroleptics

Correlations between therapeutic potency and affinity for binding D2 receptors.

[3 H]H

alop

eri d

ol b

indi

ng

IC50

(m

ol/L

)

Clinical dose of drug [mg d-1

]

haloperidol

clozapine

thiothixene

chlorpromazine

promazine

spiroperidole

Antipsychotics/Neuroleptics

• Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens.

• Clozapine has a higher affinity for the D4 receptors than for D2.

• Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).

Antipsychotics/Neuroleptics

• Antipsychotics produce catalepsy (reduce motor activity).

– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.

• Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behavior).

– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.

• Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.

– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.

hyperprolactinemia

PharmacokineticsAbsorption and Distribution

• Most antipsychotics are readily but incompletely absorbed.

• Significant first-pass metabolism.• Bioavailability is 25-65%.• Most are highly lipid soluble.• Most are highly protein bound (92-98%).• High volumes of distribution (>7 L/Kg).• Slow elimination.**Duration of action longer than expected, metabolites are present

and relapse occurs, weeks after discontinuation of drug.**

Pharmacokinetics

Metabolism

• Most antipsychotics are almost completely metabolized.

• Most have active metabolites, although not important in therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.

Pharmacokinetics

Excretion

• Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.

• Elimination half-lives are 10-24 hrs.

Antipsychotic/Neuroleptics1) Phenothiazines

Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine

Mesoridazine Acetophenazine

Carphenazine

Prochlorperazine

Trifluoperazine

• Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.

Antipsychotic/Neuroleptics

[Drug dose]

Eff

ect

Piperazine

Aliphatic

Piperidine

Antipsychotic/Neuroleptics

2) ThioxanthinesThiothixeneChlorprothixene

Closely related to phenothiazines

Antipsychotic/Neuroleptics

3) ButyrophenonesHaloperidolDroperidol*

*Not marketed in the U.S.

Antipsychotic/Neuroleptics

[Drug dose]

Eff

ect

Phenothiazine

Thioxanthene

Butyrophenone

Antipsychotics/Neuroleptics

• Newer drugs have higher affinities for D1, 5-HT or -AR receptors.

• NE, GABA, Glycine and Glutamate have also been implicated in schizophrenia.

Antipsychotics/Neuroleptics

The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.

Blockade of D2 receptors

Short term/Compensatory effects:Ý Firing rate and activity of nigrostriatal and

mesolimbic DA neurons.Ý DA synthesis, DA metabolism, DA release

Antipsychotics/Neuroleptics

Presynaptic EffectsBlockade of D2 receptors

Compensatory Effects

Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

Ý DA synthesis, DA metabolism, DA release.

Postsynaptic EffectsDepolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA neurons.

Receptor Supersensitivity

Antipsychotic/Neuroleptics

PimozideMolindoneLoxapineClozapine

OlanzapineQetiapine

RisperidoneSertindole

ZiprasidoneOlindone

Newer Drugs

Antipsychotic/Neuroleptics

ClinicalEx. Py.Drug Potency

toxicity Sedation Hypote.Chlorpromaz. Low Medium Medium High

Haloperidol High Very High Very High Low

Thiothixene High Medium Medium Medium

Clozapine Medium Very low Low Medium

Ziprasidone Medium Very Low Low Very low

Risperidone High Low Low Low

Olanzapine High Very Low Medium Very low

Sertindole High Very Low Very low Very Low

Antipsychotic/Neuroleptics

Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2

Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2

Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1

Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1

Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1

Sertindole: 5-HT2 > D2 = 1

Antipsychotic/Neuroleptics

Clinical Problems with antipsychotic drugsinclude:

1) Failure to control negative effect2) Significant toxicity

a) Parkinson-like symptomsb) Tardive Dyskinesia (10-30%)c) Autonomic effectsd) Endocrine effectse) Cardiac effects

3) Poor Concentration

The Nigro-Striatal Pathway

Inhibition

of

Motor Activity

DA

neuron ACh

neuron

GABA

neuron

GABA

neuron

Substantia

Nigra

+

-

-

-

-

Striatum

Antipsychotic/Neuroleptics

Some antipsychotics have effects at muscarinic acetylcholine receptors:

• dry mouth• blurred vision• urinary retention• constipation

ClozapineChlorpromazine

Thioridazine

Antipsychotic/Neuroleptics

Some antipsychotics have effects at -aadrenergic receptors:

• orthostatic hypotensionChlorpromazineThioridazine

Some antipsychotics have effects at H1-histaminergic receptors:

• sedationRisperidoneHaloperidol

Antipsychotic/Neuroleptics

Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.

Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome

Is a rare but serious side effect of neuroleptic (antipsychotic) therapy that can be lethal. It can arise at any time in the course of treatment and shows no predilection for age, duration of treatment, antipsychotic medication, or dose.

Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome• Occurs in pts. hypersensitive to the Ex.Py. effects of

antipsychotics.• Due to excessively rapid blockade of postsynaptic

dopamine receptors.• The syndrome begins with marked muscle rigidity. • If sweating is impaired, a fever may ensue. The

stress leukocytosis and high fever associated with this syndrome may be mistaken for an infection.

• Autonomic instability with altered blood pressure and heart rate is another midbrain manifestation.

• Creatine kinase isozymes are usually elevated, reflecting muscle damage.

Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome

Treatment Vigorous treatment with antiparkinsonian drugs is

recommended as soon as possible.Muscle relaxants such as diazepam, dantrolene or

bromocriptine may be helpful.

Antipsychotic/Neuroleptics

Drug Interactions• Additive effects with sedatives.• Additive effects with anticholinergics.• Additive effects with antihistaminergics.• Additive effects with -AR blocking drugs.• Additive effects with drugs with quinidine-like

action (thioridazine).