Antipsychotic agents By S.Bohlooli PhD

Typical neuroleptic: older agents fitting this description Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects Typical neuroleptic: older agents fitting this description Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effects

NEUROLEPTIC Drug PHENOTHIAZINES: Chlorpromazine Thioridazine TYPICAL NEUROLEPTICS: PHENOTHIAZINES: Chlorpromazine Thioridazine Fluphenazine THIOXANTHENE Thiothixene BUTYROPHENONES Haloperidol

NEUROLEPTIC Drugs Risperidone Clozapine Olanzapine Quetiapine ATYPICAL NEUROLEPTICS: Risperidone Clozapine Olanzapine Quetiapine

Figure 29-1. Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown

KEY CONCEPTS: All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability. All neuroleptics block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects. show a significant delay before they become effective. produce significant adverse effects.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system. Typical neuroleptics block the dopamine-2 receptor.

Figure 18-1. Sites of action of neuroleptics and lithium Figure 18-1. Sites of action of neuroleptics and lithium. In varicosities ("terminals") along terminal arborizations of dopamine (DA) neurons projecting from midbrain to forebrain, tyrosine is oxidized to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, then decarboxylated to DA by aromatic L-amino acid decarboxylase (AAD) and stored in vesicles. Following exocytotic release (inhibited by Li+) by depolarization in the presence of Ca2+, DA interacts with postsynaptic receptors (R) of D1 and D2 types (and structurally similar but less prevalent D1-like and D2-like receptors), as well as with presynaptic D2 and D3 autoreceptors. Inactivation of transsynaptic communication occurs primarily by active transport ("reuptake") of DA into presynaptic terminals (inhibited by many stimulants), with secondary deamination by mitochondrial monoamine oxidase (MAO). Postsynaptic D1 receptors, through Gs, activate adenylyl cyclase (AC) to increase cyclic AMP (cAMP), whereas D2 receptors inhibit AC through Gi. D2 receptors also activate receptor-operated K+ channels, suppress voltage-gated Ca2+ currents, and stimulate phospholipase C (PLC), perhaps via the bg subunits liberated from activated Gi (see Chapter 1), activating the IP3-Ca2+ pathway, thereby modulating a variety of Ca2+-dependent activities including protein kinases. Lithium inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Both Li+ and valproate can modify the abundance or function of G proteins and effectors, as well as protein kinases and several cell and nuclear regulatory factors. D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting TH, and by limiting DA release (possibly through modulation of Ca2+ or K+ currents). In contrast, presynaptic A2  adenosine receptors (A2R) activate AC and, via cyclic AMP production, TH activity. Nearly all antipsychotic agents block D2 receptors and autoreceptors; some also block D1 receptors (Table 18-2). Initially in antipsychotic treatment, DA neurons activate and release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. ER, endoplasmic reticulum.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression Abuse, addiction, physical dependence do not develop to typical neuroleptics.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.

Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS All appear equally effective; choice usually based on tolerability of side effects Most common are haloperidol ,chlorpromazine and thioridazine Latency to beneficial effects; 4-6 week delay until full response is common 70-80% of patients respond, but 30-40% show only partial response

THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Relapse, recurrence of symptoms is common ( approx. 50% within two years). Noncompliance is common. Adverse effects are common.

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension , reflex tachycardia Sedation Antihistamine effect: sedation, weight gain

KEY CONCEPT: DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS). DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM TARDIVE DYSKINESIA AKATHISIA

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Increased prolactin secretion (common with all; from dopamine blockade) Weight gain (common, antihistamine effect?) Photosensitivity (v. common w/ phenothiazines) Lowered seizure threshold (common with all) Leukopenia , agranulocytosis (rare; w/ phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines)

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine). Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS and Some Side Effects DOPAMINE-2 receptor blockade in meso- limbic and meso-cortical systems for antipsychotic effect. DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia

LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE: Dopamine neurons reduce activity. Postsynaptic D-2 receptor numbers increase (compensatory response). When D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors >> hyper- dopamine state >> tardive dyskinesia

MANAGEMENT OF EPS Dystonia and parkinsonism: anticholinergic antiparkinson drugs Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive Akathisia: benzodiazepines, propranolol Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS Adjunctive in acute manic episode Tourette’s syndrome (Haloperidole ) Control of psychosis in depressed patient Phenothiazines are effective anti-emetics, Esp. prochlorperazine Also, anti-migraine effect

GENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICS Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics

HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)

PHARMACOLOGY OF CLOZAPINE FDA-approved for patients not responding to other agents or with severe tardive dyskinesia Effective against negative symptoms Also effective in bipolar disorder Little or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-malignant syndrome; some akathisia

Blockade of alpha-1 adrenergic receptors Blockade of muscarinic cholinergic receptors Blockade of histamine-1 receptor

PHARMACOLOGY OF CLOZAPINE (Continued ) Other adverse effects; Weight gain Increased salivation Increased risk of seizures Risk of agranulocytosis requires continual monitoring

PHARMACOLOGY OF OLANZAPINE Olanzapine is clozapine without the agranulocytosis. Same therapeutic effectiveness Same side effect profile

PHARMACOLOGY OF QUETIAPINE Quetiapine is olanzapine without the anticholinergic effects. Same therapeutic effectiveness Same side effect profile

EPS incidence is dose-related Alpha-1 receptor blockade Resperidone Highly effective against positive and negative symptoms Adverse effects: EPS incidence is dose-related Alpha-1 receptor blockade Little or no anticholinergic or antihistamine effects Weight gain, PRL elevation

1st acute episode w/ + or +/- symptoms General Therapeutic Principles for Use of Neuroleptics in Schizophrenia (NIH Consensus Statement, 1999) Use typical for: 1st acute episode w/ + or +/- symptoms Switch to atypical if: Breakthrough after Rx w/ typical Use typical (depot prep) when: Patient is noncompliant

Typical; switch to Atypical General Therapeutic Principles for Use of Neuroleptics in Schizophrenia If response is inadequate to: Typical; switch to Atypical Atypical; raise dose or switch to another Atypical Typical and Atypical; switch to clozapine ® For maintenance, lifetime Rx is required.