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Psychiatric Nosology (Classification of disease) Psychosis Cognitive disorders: confusion, disorientation, memory disturbances and behavioral disorganization (delirium and dementia) Mood disorders Anxiety disorders Personality disorders

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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.

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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.

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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”.

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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.

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Etiology of Schizophrenia Idiopathic Biological Correlates Genetic Factors Neurodevelopmental abnormalities. Environmental stressors.

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Psychosis Producing Drugs Levodopa CNS stimulants Cocaine Amphetamines Khat, cathinone, methcathinone Apomorphine Phencyclidine

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Etiology of Schizophrenia Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients: Enlarge cerebral ventricles. Atrophy of cortical layers. Reduced volume of the basal ganglia.

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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.

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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.

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Pharmacodynamics Anatomic Correlates of Schizophrenia... Frontal cortex Amygdala Hippocampus Nucleus accumbens Limbic Cortex Areas Associated with Mood and Thought Processes: DA DA DA DA DA

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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.

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Dopamine System There are four major pathways for the dopaminergic system in the brain: The Nigro-Stiatal Pathway: Voluntary movements The Mesolimbic Pathway.: Behaviour The Mesocortical Pathway: Behaviour The Tuberoinfundibular Pathway: Prolactin release

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Catecholamines Tyrosine ? Tyrosine hydroxylase L-Dopa ? Dopa decarboxylase Dopamine (DA) ? Dopamine ? hydroxylase Norepinephrine (NE) (Noradrenaline) Phenylethanolamine- ? -N-methyltransferase Epinephrine (EPI) (Adrenaline)

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Dopamine Synapse DA L-DOPA Tyrosine Tyrosine

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Dopamine System DOPAMINE RECEPTORS There are at least five subtypes of receptors: Receptor D1 D2 D3 D4 D5

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Dopamine System DOPAMINE RECEPTORS Receptor 2o Messenger System D1 ?cAMP D2 ?cAMP,?K+ ch.,?Ca2+ch. D3 ?cAMP,?K+ ch.,?Ca2+ch. D4 ?cAMP D5 ?cAMP

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Dopamine Reuptake System

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Antipsychotic treatments SCHIZOPHRENIA IS FOR LIFE There is no remission

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Antipsychotic treatments Schizophrenia 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.

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Antipsychotic treatments 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 Rhone-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.

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Antipsychotics treatment Antipsychotics/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.

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Antipsychotics/Neuroleptics Although 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.

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Antipsychotics/Neuroleptics NON-compliance is the major reason for relapse.

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Antipsychotic/Neuroleptics Three major groups : Phenothiazines Thioxanthine Butyrophenones OLDER DRUGS

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Antipsychotic/Neuroleptics Phenothiazines Chlorpromazine Thioridazine Fluphenazine Trifluopromazine Piperacetazine Perfenazine Mesoridazine Acetophenazine Carphenazine Prochlorperazine Trifluoperazine Aliphatic Piperidine Piperazine* * Most likely to cause extrapyramidal effects.

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Antipsychotic/Neuroleptics 2) Thioxanthines Thiothixene Chlorprothixene Closely related to phenothiazines

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Antipsychotic/Neuroleptics 3) Butyrophenones Haloperidol Droperidol* *Not marketed in the USA

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Atypical Antipsychotic Pimozide Atypical Antipsychoitcs Loxapine Clozapine Olanzapine Qetiapine Indolones Sertindole Ziprasidone Olindone Molindone Risperidone

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Classification of antipsychotic drugs:

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

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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.

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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).

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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

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Pharmacokinetics Absorption 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.**

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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.

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Pharmacokinetics Excretion Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged. Elimination half-lives are 10-24 hrs.

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Antipsychotic/Neuroleptics [Drug dose] Effect Piperazine Aliphatic Piperidine

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Antipsychotic/Neuroleptics [Drug dose] Effect Phenothiazine d. Thioxanthene d. Butyrophenone d.

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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.

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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: Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release

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Antipsychotics/Neuroleptics Presynaptic Effects Blockade of D2 receptors ? Compensatory Effects Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release. Postsynaptic Effects Depolarization Blockade Inactivation of nigrostriatal and mesolimbic DA neurons. ? Receptor Supersensitivity

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Antipsychotic/Neuroleptics Clinical Ex. 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

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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

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Antipsychotic/Neuroleptics Clinical Problems with antipsychotic drugs include: Failure to control negative effect Significant toxicity Neurological effects Autonomic effects Endocrine effects Cardiac effects 3) Poor Concentration

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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

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Acute dystonia

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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

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The Nigro-Striatal Pathway

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Antipsychotic/Neuroleptics Some antipsychotics have effects at muscarinic acetylcholine receptors: Dry mouth Blurred vision Urinary retention Constipation Clozapine Chlorpromazine Thioridazine

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Antipsychotic/Neuroleptics Some antipsychotics have effects at a-adrenergic receptors: orthostatic hypotension Chlorpromazine Thioridazine Some antipsychotics have effects at H1-histaminergic receptors: sedation Risperidone Haloperidol

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

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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

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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.

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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.

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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.

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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).

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XVI. Anti-Manic Drugs Lithium (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 acid 3) Calcium-channel blockers (nifendipine, diltiazem, verapamil).

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XVI. Anti-Manic Drugs Li+ Small monovalent cation (between H+ and Na+). Distributed in total body water, similar to sodium. May partially inhibit Na+-K+ ATPase. Inhibits ADH => diuresis. May decrease thyroid function. Teratogenic (tricuspid valve malformation). Excreted by kidney.

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XVI. Anti-Manic Drugs Li+ Not to be taken with thiazide diuretics (e.g. chlorthiazide). Lithium clearance is reduced by 25%. All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium.

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XVI. Anti-Manic Drugs Li+ Helps alleviate the depressive phase of bipolar illness. Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.

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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.

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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.

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XVI. Anti-Manic Drugs PIP PIP2 G IP3 IP2 IP1 Inositol PI X Li+ PLC DAG Ca 2+

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XVI. Anti-Manic Drugs Valproic Acid A well known antiepileptic has been found to have antimanic effects. Shows efficacy equivalent as that of lithium during the early weeks of treatment and is being evaluated for maintenance treatment. Titrated well, the sedation can be controlled. Nausea being the only limiting factor in some patients. May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients. Mechanism of action: ???

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XVI. Anti-Manic Drugs Carbamazepine Effective as an antimania medication Mechanism of action (Con’t): May be due to decrease overexcitability of neurons (anticonvulsive effect).

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XVI. Anti-Manic Drugs Ca2+ Channel blockers Nifedeipine Verapamil Mechanism of action (Con’t): NT Release?