DRUG TREATMENT OF PSYCHOSIS

Psychiatric Nosology(Classification of disease)

• Psychosis• Cognitive disorders: confusion, disorientation,

memory disturbances and behavioral disorganization (delirium and dementia)

• Mood disorders• Anxiety disorders• Personality disorders

Psychosis• Psychosis is a thought disorder

characterized by :• Disturbances of reality and perception• Impaired cognitive functioning• 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.

Schizophrenia

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

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

changes.

Schizophrenia• It is a thought disorder.

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

• It may involved 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 (Loss of the capacity to experience pleasure), 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.

Psychosis Producing Drugs

1) Levodopa2) CNS stimulants

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

3) Apomorphine 4) Phencyclidine

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.

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.

Dopamine Theory of Schizophrenia

Evidence against the hypothesis• 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: Voluntary movementsII. The Mesolimbic Pathway.: BehaviourIII. The Mesocortical Pathway: Behaviour IV. The Tuberoinfundibular Pathway: Prolactin release

THE DOPAMINERGIC SYSTEM

•THE DOPAMINERGIC SYSTEM

CatecholaminesTyrosine

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 five subtypes of receptors:ReceptorD1D2D3D4D5

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 devise:

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.

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 is lifelong and it is preferable to prevent the psychotic episodes than to treat them.

Antipsychotics/NeurolepticsAlthough the antipsychotic/neuroleptics are drugs used mainly in the treatment of schizophrenia, they are also used in the treatment of :– Psychoses associated with depression – Manic-depressive illness– 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. Phenothiazines 2. Thioxanthine3. Butyrophenones

OLDER DRUGS

Antipsychotic/Neuroleptics

1) Phenothiazines

Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine

Mesoridazine Acetophenazine

Carphenazine

Prochlorperazine

Trifluoperazine

• Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.

Antipsychotic/Neuroleptics

2) ThioxanthinesThiothixeneChlorprothixene

Closely related to phenothiazines

Antipsychotic/Neuroleptics

3) ButyrophenonesHaloperidolDroperidol*

*Not marketed in the USA

Atypical Antipsychotic

PimozideAtypical Antipsychoitcs

LoxapineClozapineOlanzapineQetiapine

IndolonesSertindole

ZiprasidoneOlindone

MolindoneRisperidone

Antipsychotics/Neuroleptics• Old

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

Dopamine Synapse

DA

L-DOPA

TyrosineTyrosine

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.

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

Antipsychotic/Neuroleptics

[Drug dose]

Effe

ct

Piperazine

Aliphatic

Piperidine

Antipsychotic/Neuroleptics

[Drug dose]

Effe

ct

Phenothiazine d.

Thioxanthene d.

Butyrophenone d.

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/NeurolepticsThe 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/NeurolepticsPresynaptic Effects

Blockade of D2 receptors

Compensatory EffectsÝ 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

Clinical Problems with antipsychotic drugsinclude:

1) Failure to control negative effect2) Significant toxicity

a) Neurological effectsb) Autonomic effectsc) Endocrine effectsd) Cardiac effects

3) Poor Concentration

Neurological effects• Acute dystonia- Spasms of muscles of tongue,

neck and face• Akasthisia – Uncontrolled motor restlessness• Parkinsonism• Neuroleptic Mallignant Syndrome• Rabbit syndrome (perioral tremors)• Tardive dyskinesia

Piperazines

Butyrophenones

Acute dystonia

Tardive Dyskinesia (TD)

• Repetitive involuntary movements, lips, jaw, and tongue

• Choreiform quick movements of the extremities

• As with Parkinson’s, movements stop during sleep

• No effective treatment

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 -adrenergic 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.

Blood Dyscrasias

• Clozapine 1-3 % incidence agranulocytosis• Monitor WBC weekly

– WBC < 3,000 hold tx, check for infection– Restart when reach 3,500– WBC < 2,000 discontinue treatment, do not

rechallange

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/NeurolepticsNeuroleptic 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.

XVI. Anti-Manic DrugsLithium (Li+) remains the drug of choice for the

treatment and prophylaxis of mania.• Acute manic episodes are managed with lithium

salts (carbonate or citrate) alone, or in combination with:

1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression).

2) Valproic acid3) Calcium-channel blockers (nifendipine,

diltiazem, verapamil).

XVI. Anti-Manic DrugsLi+

• Helps alleviate the depressive phase of bipolar illness.

• Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.

XVI. Anti-Manic Drugs

Li+Mechanism of action:• Does not alter receptor numbers but alters the

coupling of the receptors with their second messengers by reducing coupling of G-proteins.

• Regulation of -AR and DAR.• Can reduce release of NTs (5-HT) and affinity of

binding to receptor.

XVI. Anti-Manic Drugs

Li+Mechanism of action (Con’t):Inhibits breakdown of IP2 to IP1 (during PIP

hydrolysis) => depletion of DAG and IP3 and [Ca2+] in response to receptor activation (i.e. from 5-HT2R, 1-AR, muscarinic receptors and others).

• Alterations in adenylate cyclase and phospholipase C.

XVI. Anti-Manic Drugs

PIP

PIP2

G IP3

IP2

IP1

InositolPI

X Li+

PLC

DAG

Ca 2+