chapter 29: antipsychotic agents. introduction the term psychosis refers to a variety of mental...

Chapter 29:Chapter 29:Antipsychotic AgentsAntipsychotic Agents

IntroductionIntroduction

• The term psychosis refers to a variety of mental The term psychosis refers to a variety of mental disorders characterized by one or more of the disorders characterized by one or more of the following symptoms: following symptoms:

1)1) Diminished and distorted capacity to process Diminished and distorted capacity to process information and draw logical conclusions information and draw logical conclusions

2)2) HallucinationsHallucinations, usually auditory or visual, but , usually auditory or visual, but sometimes tactile or olfactorysometimes tactile or olfactory

3)3) Delusions (false believes)Delusions (false believes)4)4) Incoherence or marked loosening of Incoherence or marked loosening of

associationsassociations5)5) Catatonic or disorganized behaviorCatatonic or disorganized behavior6)6) Aggression or violenceAggression or violence

IntroductionIntroduction

• The psychotic disorders include schizophrenia, The psychotic disorders include schizophrenia, the manic phase of bipolar (manic-depressive) the manic phase of bipolar (manic-depressive) illness, acute idiopathic psychotic illnesses, and illness, acute idiopathic psychotic illnesses, and other conditions marked by severe agitationother conditions marked by severe agitation

Nature of Psychosis & SchizophreniaNature of Psychosis & Schizophrenia

• Schizophrenia is a particular type of psychosis Schizophrenia is a particular type of psychosis characterized mainly by a clear sensorium but characterized mainly by a clear sensorium but a marked thinking disturbancea marked thinking disturbance

• Because it affects young people, is often Because it affects young people, is often chronic and is usually highly disablingchronic and is usually highly disabling

• There is a strong hereditary factor in its There is a strong hereditary factor in its aetiology, and evidence suggestive of a aetiology, and evidence suggestive of a fundamental biological disorder fundamental biological disorder (neurodevelopmental disorder)(neurodevelopmental disorder)


• The main clinical features of the disease are:The main clinical features of the disease are:• Positive symptoms: Positive symptoms: – Delusions (often paranoid in nature) Delusions (often paranoid in nature) – Hallucinations, usually in the form of voices which are often Hallucinations, usually in the form of voices which are often

exhortatory in their message exhortatory in their message – Thought disorder, comprising wild trains of thought, garbled Thought disorder, comprising wild trains of thought, garbled

sentences and irrational conclusions, sometimes associated sentences and irrational conclusions, sometimes associated with the feeling that thoughts are inserted or withdrawn by with the feeling that thoughts are inserted or withdrawn by an outside agency an outside agency

– Abnormal behaviours, such as stereotyped movements and Abnormal behaviours, such as stereotyped movements and occasionally aggressive behavioursoccasionally aggressive behaviours

• Negative symptoms: Negative symptoms: – Withdrawal from social contacts Withdrawal from social contacts – Flattening of emotional responsesFlattening of emotional responses– Lack of motivationLack of motivation


• The clinical phenotype varies greatly, The clinical phenotype varies greatly, particularly with respect to the balance particularly with respect to the balance between negative and positive symptomsbetween negative and positive symptoms

• The pathogenesis of schizophrenia is The pathogenesis of schizophrenia is unknownunknown

• Pharmacological evidence is consistent with Pharmacological evidence is consistent with DA hyperactivity hypothesis. There is also DA hyperactivity hypothesis. There is also evidence of glutamate & 5-HT involvement evidence of glutamate & 5-HT involvement

• Schizophrenia has familial incidence Schizophrenia has familial incidence

Neurochemical theoriesNeurochemical theories

• Came mainly from analyzing the effects of Came mainly from analyzing the effects of antipsychotic and propsychotic drugs-from antipsychotic and propsychotic drugs-from pharmacology rather than from neurochemistrypharmacology rather than from neurochemistry

• The main neurochemical theories centre on The main neurochemical theories centre on dopamine and glutamate, although other dopamine and glutamate, although other mediators, particularly 5-HT, are also receiving mediators, particularly 5-HT, are also receiving attention attention


I.I. The Dopamine theory of schizophreniaThe Dopamine theory of schizophrenia• It is based on multiple lines of evidence It is based on multiple lines of evidence

suggesting that excessive dopaminergic activity suggesting that excessive dopaminergic activity underlies schizophreniaunderlies schizophrenia

• It is still highly relevant to understanding the It is still highly relevant to understanding the major dimensions of schizophrenia, such as major dimensions of schizophrenia, such as positive and negative symptoms, cognitive positive and negative symptoms, cognitive impairment, and possibly depressionimpairment, and possibly depression


I.I. The Dopamine theory of schizophreniaThe Dopamine theory of schizophrenia• It is also essential to understanding the MOA of It is also essential to understanding the MOA of

most and probably all antipsychotic drugsmost and probably all antipsychotic drugs

• However, the dopamine hypothesis is far from a However, the dopamine hypothesis is far from a complete explanation of all aspects of complete explanation of all aspects of schizophrenia, especially the cognitive schizophrenia, especially the cognitive impairmentimpairment

The Serotonin Hypothesis of SchizophreniaThe Serotonin Hypothesis of Schizophrenia

II.II. The Serotonin theory of schizophreniaThe Serotonin theory of schizophrenia• It has been found that 5-HTIt has been found that 5-HT2A2A-receptor blockade -receptor blockade

is a key factor in the mechanism of action of the is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such main class of atypical antipsychotic drugs such as clozapine and quetiapineas clozapine and quetiapine

• 5-HT5-HT2A2A-receptors modulate the release of -receptors modulate the release of

dopamine, norepinephrine, glutamate, GABA dopamine, norepinephrine, glutamate, GABA and acetylcholine in the cortex, limbic region, and acetylcholine in the cortex, limbic region, and striatumand striatum


III.III. The Glutamate theory of schizophreniaThe Glutamate theory of schizophrenia• Glutamate is the major excitatory Glutamate is the major excitatory

neurotransmitter in the brainneurotransmitter in the brain

• Phencyclidine and ketamine are noncompetitive Phencyclidine and ketamine are noncompetitive inhibitors of the N-methyl-D-aspartate (NMDA) inhibitors of the N-methyl-D-aspartate (NMDA) receptor can exacerbate both cognitive receptor can exacerbate both cognitive impairment and psychosis in patients with impairment and psychosis in patients with schizophreniaschizophrenia

• Hypofunction of NMDA receptors, located on Hypofunction of NMDA receptors, located on GABAergic interneurons contributed to GABAergic interneurons contributed to schizophreniaschizophrenia

Antipsychotic AgentsAntipsychotic Agents

• Are able to reduce psychotic symptoms in a wide Are able to reduce psychotic symptoms in a wide variety of conditions, including variety of conditions, including schizophreniaschizophrenia, , bipolar disorder, psychotic depression, senile bipolar disorder, psychotic depression, senile psychoses, various organic psychoses, and drug-psychoses, various organic psychoses, and drug-induced psychosesinduced psychoses

• They are also able to improve mood and reduce They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patientsthe primary disturbance in nonpsychotic patients


• Their antipsychotic actions appear to reflect a Their antipsychotic actions appear to reflect a blockade at dopamine and/or serotonin blockade at dopamine and/or serotonin receptorsreceptors

• Many of these agents also block cholinergic, Many of these agents also block cholinergic, adrenergic, and histaminergic receptors. The adrenergic, and histaminergic receptors. The undesirable side effects of these agents are undesirable side effects of these agents are often a result of actions at these other often a result of actions at these other receptorsreceptors


Atypical antipsychotic Atypical antipsychotic drugsdrugs

LoxapineClozapine* Asenapine Olanzapine Quetiapine Paliperidone Risperidone Sertindole

Ziprasidone ZotepineAripiprazole

Typical antipsychoticTypical antipsychotic DrugsDrugs

a) Low Potency a) Low Potency ChlorpromazineChlorpromazine

ThioridazineThioridazineThiothixeneThiothixene

ProchlorperazineProchlorperazine

b) High potencyb) High potencyHaloperidolHaloperidol

PimozidePimozideMolindoneMolindone

FluphenazineFluphenazine

Dopaminergic SystemsDopaminergic Systems

• Five dopaminergic systems or pathways are Five dopaminergic systems or pathways are important for understanding schizophrenia and the important for understanding schizophrenia and the mechanism of action of antipsychotic drugs:mechanism of action of antipsychotic drugs:

1)1) Mesolimbic-mesocortical pathway: Mesolimbic-mesocortical pathway: the one the one most closely related to behavior and psychosismost closely related to behavior and psychosis

2)2) Nigrostriatal pathway: Nigrostriatal pathway: it is involved in the it is involved in the coordination of voluntary movement. Blockade of coordination of voluntary movement. Blockade of the D2 receptors in the nigrostriatal pathway is the D2 receptors in the nigrostriatal pathway is responsible for EPSresponsible for EPS

Dopaminergic SystemsDopaminergic Systems

3)3) Tuberoinfundibular system: Tuberoinfundibular system: it releases it releases dopamine into the pituitary portal circulation. dopamine into the pituitary portal circulation. Dopamine released by these neurons Dopamine released by these neurons physiologically inhibits prolactin secretion from physiologically inhibits prolactin secretion from the anterior pituitarythe anterior pituitary

4)4) Medullary-periventricular pathway: Medullary-periventricular pathway: it may be it may be involved in eating behaviorinvolved in eating behavior

5)5) Incertohypothalamic pathway: Incertohypothalamic pathway: It appears to It appears to regulate the anticipatory motivational phase of regulate the anticipatory motivational phase of copulatory behavior in ratscopulatory behavior in rats

Mechanism of actionMechanism of action

1)1) Typical antipsychotic agentsTypical antipsychotic agents• The clinical efficacy of the typical neuroleptic The clinical efficacy of the typical neuroleptic

drugs correlates closely with their relative ability drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system to block D2 receptors in the mesolimbic system of the brainof the brain

• The binding affinity of the typical is very strongly The binding affinity of the typical is very strongly correlated with clinical antipsychotic and correlated with clinical antipsychotic and extrapyramidal potency: the typical antipsychotic extrapyramidal potency: the typical antipsychotic drugs must be given in sufficient doses to drugs must be given in sufficient doses to achieve 60% occupancy of striatal D2 receptorsachieve 60% occupancy of striatal D2 receptors


1)1) Typical antipsychotic agentsTypical antipsychotic agents• These drugs vary in potency: chlorpromazine is a These drugs vary in potency: chlorpromazine is a

low-potency drug, and fluphenazine is a high-low-potency drug, and fluphenazine is a high-potency agent potency agent

• No one drug is clinically more effective than No one drug is clinically more effective than anotheranother


1)1) Typical antipsychotic agentsTypical antipsychotic agents• Antagonism of the of dopamine in the Antagonism of the of dopamine in the

nigrostriatal system is the major factor in the nigrostriatal system is the major factor in the extrapyramidal side effects (EPS) seen with extrapyramidal side effects (EPS) seen with these agentsthese agents

• EPS are produced when the occupancy of striatal EPS are produced when the occupancy of striatal D2 receptors reaches 80% or higherD2 receptors reaches 80% or higher

• Antagonism of dopamine’s neurohormonal action Antagonism of dopamine’s neurohormonal action in the anterior pituitary accounts for the in the anterior pituitary accounts for the hyperprolactinemia associated with antipsychotic hyperprolactinemia associated with antipsychotic administrationadministration


2)2) Atypical antipsychotic drugsAtypical antipsychotic drugs• These drugs have complex pharmacology but These drugs have complex pharmacology but

they share a greater ability to alter 5-HT2A-they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor receptor activity than to interfere with D2-receptor actionaction

• They do not have very high affinity for the DThey do not have very high affinity for the D22

receptor: effective at lower occupancy levels of receptor: effective at lower occupancy levels of the dopamine receptors (30–50%)the dopamine receptors (30–50%)

• The posses high occupancy of 5-HTThe posses high occupancy of 5-HT2A 2A receptorsreceptors

• As a result, they have fewer extrapyramidal As a result, they have fewer extrapyramidal adverse effects than the older, traditional agentsadverse effects than the older, traditional agents


2)2) Atypical antipsychotic drugsAtypical antipsychotic drugs• Atypical antipsychotic drugs are inverse agonists Atypical antipsychotic drugs are inverse agonists

of the 5-HT2A receptor; that is, they block the of the 5-HT2A receptor; that is, they block the constitutive activity of these receptorsconstitutive activity of these receptors

• In most cases, they act as partial agonists at the In most cases, they act as partial agonists at the 5-HT1A receptor, which produces synegistic 5-HT1A receptor, which produces synegistic effects with 5-HT2A receptor antagonismeffects with 5-HT2A receptor antagonism

Differences among Antipsychotic DrugsDifferences among Antipsychotic Drugs

• All effective antipsychotic drugs block DAll effective antipsychotic drugs block D22

receptors, the degree of this blockade in relation receptors, the degree of this blockade in relation to other actions on receptors varies considerably to other actions on receptors varies considerably among drugsamong drugs

• Most of the newer atypical agents appear to exert Most of the newer atypical agents appear to exert part of their unique action through inhibition of part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HTserotonin receptors (5-HT), particularly 5-HT2A2A

receptorsreceptors

• The antipsychotics also have variable antagonist The antipsychotics also have variable antagonist actions at muscarinic, actions at muscarinic, αα-adrenergic, and -adrenergic, and histaminergic receptors in brain and peripheral histaminergic receptors in brain and peripheral tissuetissue

D2 α1 H1 M 5H2A EPS Adverse effectsFirst generationChlorpromazine +++ +++ ++ ++ ++ ++ Increased prolactin (gynaecomastia)

Hypothermia Anticholinergic effectsHypersensitivity reactionsObstructive jaundice

Thioridazine ++ +++ + ++ ++ + As chlorpromazine but does not cause jaundice

Haloperidol +++ ++ - ± + +++ As chlorpromazine but does not cause jaundice Fewer anticholinergic side effects

Flupenthixol +++ ++ ++ - +++ ++ Increased prolactin (gynaecomastia)Restlessness

D2 α1 H1 M 5H2A EPS Adverse effectsSecond generationSulpiride +++ - - - - + Increased prolactin (gynaecomastia)

Clozapine ++ ++ ++ ++ +++ - Risk of agranulocytosis ( 1%): regular ∼blood counts requiredSeizuresSedationSalivationAnticholinergic side effectsWeight gain

D2 α1 H1 M 5H2A EPS Adverse effectsSecond generationRisperidone ++ ++ ++ ++ +++ + Weight gain

EPS at high dosesHypotension

Sertindole ++ ++ - - +++ + Ventricular arrhythmias (ECG checks advisable)Weight gainNasal congestion

Quetiapine + +++ - + + + TachycardiaAgitationDry mouthWeight gain

Aripiprazole +++)PA(*

+ + - ++ - -

Zotepine ++ + + + + - Weight gainHypotensionCardiac dysrhythmias

Clinical UsesClinical Uses

A.A. Psychiatric Indications (schizophrenia)Psychiatric Indications (schizophrenia)

• The principal goals for the management of a The principal goals for the management of a chronic schizophrenic disorder are the chronic schizophrenic disorder are the minimizing of symptoms and the prevention of minimizing of symptoms and the prevention of exacerbationsexacerbations

• All of the antipsychotic drugs can reduce the All of the antipsychotic drugs can reduce the hallucinations and delusions (positive symptoms) hallucinations and delusions (positive symptoms) associated with by blocking dopamine receptors associated with by blocking dopamine receptors in the mesolimbic system of the brainin the mesolimbic system of the brain

• No one drug or combination of drugs selectively No one drug or combination of drugs selectively affects a particular symptom complexaffects a particular symptom complex


A.A. Psychiatric Indications (schizophrenia)Psychiatric Indications (schizophrenia)• For approximately 70% of patients with For approximately 70% of patients with

schizophrenia typical and atypical antipsychotic schizophrenia typical and atypical antipsychotic drugs are of equal efficacy for treating positive drugs are of equal efficacy for treating positive symptomssymptoms

• Atypical drugs ameliorate the negative Atypical drugs ameliorate the negative symptoms and cognition, diminished risk of symptoms and cognition, diminished risk of tardivedyskinesia and other forms of EPS, and tardivedyskinesia and other forms of EPS, and are favored for lesser increases in prolactin are favored for lesser increases in prolactin levelslevels


A.A. Psychiatric Indications (schizophrenia)Psychiatric Indications (schizophrenia)• Drug choice is determined mainly by the Drug choice is determined mainly by the

patient’s past responses and the drug’s potential patient’s past responses and the drug’s potential for producing adverse effectsfor producing adverse effects

• The clinical trend is to prescribe the higher-The clinical trend is to prescribe the higher-potency atypical agentspotency atypical agents

• Other indications for the use of antipsychotics Other indications for the use of antipsychotics include: include:

• Tourette's syndrome in patients with Tourette's syndrome in patients with Alzheimer's diseaseAlzheimer's disease

• psychotic depression (with antidepressants)psychotic depression (with antidepressants)


A.A. Psychiatric Indications (schizophrenia)Psychiatric Indications (schizophrenia)• Other indications for the use of antipsychotics Other indications for the use of antipsychotics

include: include:

a)a) Tourette's syndrome Tourette's syndrome

b)b) Disturbed behavior in patients with Disturbed behavior in patients with Alzheimer's diseaseAlzheimer's disease

c)c) Psychotic depression (with antidepressants)Psychotic depression (with antidepressants)

Clinical usesClinical uses

B. Nonpsychiatric IndicationsB. Nonpsychiatric Indications1.1. Antiemetics Antiemetics • Prochlorperazine & benzquinamide are useful in Prochlorperazine & benzquinamide are useful in

the treatment of drug-induced nauseathe treatment of drug-induced nausea

• This action is due to DA receptor blockade, both This action is due to DA receptor blockade, both centrally (in CTZ of the medulla) & peripherally centrally (in CTZ of the medulla) & peripherally (on receptors in the stomach) (on receptors in the stomach)

• The atypical antipsychotic drugs are not used as The atypical antipsychotic drugs are not used as antiemeticsantiemetics

Clinical usesClinical uses

B. Nonpsychiatric IndicationsB. Nonpsychiatric Indications

1.1. Antipruritic: Antipruritic: some phenothiazines with some phenothiazines with considerable H1 receptor-blocking action e.g considerable H1 receptor-blocking action e.g prochlorperazineprochlorperazine

2.2. Preoperative sedation Preoperative sedation (promethazine)(promethazine)

3.3. NeuroleptanesthesiaNeuroleptanesthesia (droperidol) (droperidol)

Adverse reactionsAdverse reactions

• Antipsychotic drugs are characterized by high Antipsychotic drugs are characterized by high therapeutic indices with respect to mortality, but therapeutic indices with respect to mortality, but side effects occur routinely at therapeutic doses, side effects occur routinely at therapeutic doses, mostly as extensions of pharmacological actionsmostly as extensions of pharmacological actions

• The characteristic neurological symptoms caused The characteristic neurological symptoms caused by these agents are particularly troublesome, by these agents are particularly troublesome, often limit the tolerated dose, and may interfere often limit the tolerated dose, and may interfere with the desired benefits and patient compliancewith the desired benefits and patient compliance

Adverse ReactionsAdverse Reactions

A.A. Behavioral EffectsBehavioral Effects• The older typical antipsychotic drugs are unpleasant The older typical antipsychotic drugs are unpleasant

to taketo take

• Many patients may experience "pseudodepression" Many patients may experience "pseudodepression" due to drug-induced akinesia usually responds to due to drug-induced akinesia usually responds to treatment with antiparkinsonism drugstreatment with antiparkinsonism drugs

• Pseudodepressions may be due to higher doses than Pseudodepressions may be due to higher doses than needed in a partially remitted patient, in which case needed in a partially remitted patient, in which case decreasing the dose may relieve the symptomsdecreasing the dose may relieve the symptoms

• Toxic-confusional states with very high doses of Toxic-confusional states with very high doses of drugs that have prominent antimuscarinic actionsdrugs that have prominent antimuscarinic actions


B.B. Extrapyramidal side effects (EPS)Extrapyramidal side effects (EPS)• The inhibitory effects of dopaminergic neurons are The inhibitory effects of dopaminergic neurons are

normally balanced by the excitatory actions of normally balanced by the excitatory actions of cholinergic neurons in the striatumcholinergic neurons in the striatum

• Blocking dopamine receptors alters this balance, Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence, causing a relative excess of cholinergic influence, which results in extrapyramidal motor effectwhich results in extrapyramidal motor effect

• Two extrapyramidal conditions, acute dystonic Two extrapyramidal conditions, acute dystonic reactions (spastic retrocollis or torticollis) and reactions (spastic retrocollis or torticollis) and akathisia (uncontrollable restlessness), occur early akathisia (uncontrollable restlessness), occur early during treatment, while parkinsonism tends to evolve during treatment, while parkinsonism tends to evolve gradually over days to weeksgradually over days to weeks


B.B. Extrapyramidal side effects (EPS) Extrapyramidal side effects (EPS) • Occur most commonly with the high-potency Occur most commonly with the high-potency

typical antipsychotics (e.g. haloperidol and typical antipsychotics (e.g. haloperidol and fluphenazine)fluphenazine)

• Drugs that exhibit strong anticholinergic activity, Drugs that exhibit strong anticholinergic activity, such as thioridazine (low-potency typical), show such as thioridazine (low-potency typical), show fewer EPS, because the cholinergic activity is fewer EPS, because the cholinergic activity is strongly dampenedstrongly dampened


B.B. Extrapyramidal side effects (EPS) Extrapyramidal side effects (EPS) • Atypical antipsychotics (clozapine and Atypical antipsychotics (clozapine and

risperidone) exhibit a lower potential for risperidone) exhibit a lower potential for causing extrapyramidal symptoms, which causing extrapyramidal symptoms, which has been attributed to their blockade of 5-has been attributed to their blockade of 5-HT2A receptorsHT2A receptors


B. Extrapyramidal side effects (EPS)B. Extrapyramidal side effects (EPS)• Parkinsonism can be treated with antimuscarinic Parkinsonism can be treated with antimuscarinic

drugs (e.g. benzotropine), or amantadine. drugs (e.g. benzotropine), or amantadine. (Levodopa should never be used in these (Levodopa should never be used in these patients)patients)

• Akathisia and dystonic reactions preferably Akathisia and dystonic reactions preferably treated with a sedative antihistamine with treated with a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orallywhich can be given either parenterally or orally


C.C. Tardive dyskinesiaTardive dyskinesia• The most important unwanted effect of The most important unwanted effect of

antipsychotic drugsantipsychotic drugs

• Develops after months or years in 20-40% of Develops after months or years in 20-40% of patients treated with first-generation patients treated with first-generation antipsychotic drugsantipsychotic drugs

• Patients display involuntary movements, Patients display involuntary movements, including lateral jaw movements and “fly-including lateral jaw movements and “fly-catching” motions of the tonguecatching” motions of the tongue


C.C. Tardive dyskinesiaTardive dyskinesia• Its seriousness lies in the fact that it is a Its seriousness lies in the fact that it is a

disabling and often irreversible conditiondisabling and often irreversible condition

• It is caused by relative cholinergic deficiency It is caused by relative cholinergic deficiency secondary to supersensitivity of DA receptors in secondary to supersensitivity of DA receptors in the caudate-putamen (D2-receptor up-the caudate-putamen (D2-receptor up-regulation?)regulation?)

• Appropriately managed by reducing the dose or Appropriately managed by reducing the dose or to switch to one of the newer atypical agents to switch to one of the newer atypical agents ((quetiapine or clozapine, the atypical agents with quetiapine or clozapine, the atypical agents with the least likelihood of causing tardive dyskinesiathe least likelihood of causing tardive dyskinesia))


D.D. Neurologic EffectsNeurologic Effects• Neuroleptic malignant syndrome is a rare Neuroleptic malignant syndrome is a rare

medical emergency occurs in patients who are medical emergency occurs in patients who are extremely sensitive to the EPS of antipsychotic extremely sensitive to the EPS of antipsychotic agents agents

• It occurs in about 1% of patients receiving It occurs in about 1% of patients receiving antipsychotic and about 10% of these cases are antipsychotic and about 10% of these cases are fatalfatal

• It is characterized by muscle rigidity, fever as a It is characterized by muscle rigidity, fever as a result of sweating impairment, altered mental result of sweating impairment, altered mental status and stupor, unstable blood pressure, and status and stupor, unstable blood pressure, and myoglobinemiamyoglobinemia


D.D. Neurologic EffectsNeurologic Effects• Muscle-type creatine kinase levels are usually Muscle-type creatine kinase levels are usually

elevated, reflecting muscle damageelevated, reflecting muscle damage

• This syndrome is believed to result from an This syndrome is believed to result from an excessively rapid blockade of postsynaptic excessively rapid blockade of postsynaptic dopamine receptorsdopamine receptors

• Treatment necessitates discontinuation of the Treatment necessitates discontinuation of the antipsychoyic drug and supportive therapyantipsychoyic drug and supportive therapy


C. Autonomic Nervous System Effects C. Autonomic Nervous System Effects • Antipsychotics have variable antagonistic Antipsychotics have variable antagonistic

interactions at peripheral adrenergic, cholinergic, interactions at peripheral adrenergic, cholinergic, and histsmine receptors; thus, the drugs’ effects and histsmine receptors; thus, the drugs’ effects on the ANS are complex and unpredictableon the ANS are complex and unpredictable

1)1) α-α-adrenergic-blocking actions adrenergic-blocking actions (chlorpromazine, (chlorpromazine, mesoridazine): orthostatic hypotension or mesoridazine): orthostatic hypotension or impaired ejaculationimpaired ejaculation


C. Autonomic Nervous System Effects C. Autonomic Nervous System Effects

2)2) Antimuscarinic effects Antimuscarinic effects (thioridazine, (thioridazine, chlorpromazine, clozapine, and olanzapine): chlorpromazine, clozapine, and olanzapine): blurred vision, dry mouth (exception: clozapine blurred vision, dry mouth (exception: clozapine increase salivation), confusion, constipation, and increase salivation), confusion, constipation, and urinary retentionurinary retention


E.E. Toxic or Allergic Reactions: Toxic or Allergic Reactions: 1)1) Agranulocytosis: Agranulocytosis: clozapine in ~1-2%. clozapine in ~1-2%.

• Because of the risk, weekly blood counts are Because of the risk, weekly blood counts are mandatory for patients receiving clozapine for mandatory for patients receiving clozapine for the first 6 months of treatment and every 3 the first 6 months of treatment and every 3 weeks thereafterweeks thereafter

2)2) Cholestatic jaundice Cholestatic jaundice

3)3) Urticarial skin reactions Urticarial skin reactions (common but (common but usually mild)usually mild)


F.F. Metabolic & Endocrine EffectsMetabolic & Endocrine Effects1)1) Weight gain, especially with clozapine and Weight gain, especially with clozapine and

olanzapine, and requires monitoring of food olanzapine, and requires monitoring of food intake, especially carbohydratesintake, especially carbohydrates

2)2) Hyperglycemia Hyperglycemia secondary to weight gain-secondary to weight gain-associated insulin resistance associated insulin resistance

3)3) HyperlipidemiaHyperlipidemia


F.F. Metabolic & Endocrine EffectsMetabolic & Endocrine Effects• Endocrine changes occur because of effects Endocrine changes occur because of effects

of antipsychotic drugs on the hypothalamus of antipsychotic drugs on the hypothalamus or pituitary, including their antidopaminergic or pituitary, including their antidopaminergic actionsactions

• In the pituitary, older typical antipsychotic In the pituitary, older typical antipsychotic drugs, as well as risperidone and drugs, as well as risperidone and paliperidone, block D2 receptors, leading to paliperidone, block D2 receptors, leading to an increase in prolactin releasean increase in prolactin release


F.F. Metabolic & Endocrine EffectsMetabolic & Endocrine Effects• Atypical neuroleptics are less likely to Atypical neuroleptics are less likely to

produce prolactin elevations because their produce prolactin elevations because their diminished D2 antagonismdiminished D2 antagonism

• Amenorrhea and increased libido have been Amenorrhea and increased libido have been reported in women, whereas decreased libido reported in women, whereas decreased libido and gynecomastia have been observed in and gynecomastia have been observed in menmen


G.G. Ocular Complications: Ocular Complications: 1)1) Opacities of the cornea and lens: Opacities of the cornea and lens: due to due to

deposition the anterior portions of the eye deposition the anterior portions of the eye are a common complication of are a common complication of chlorpromazine therapychlorpromazine therapy

2)2) Pigmentary retinopathyPigmentary retinopathy associated with associated with "browning" of vision: high doses of "browning" of vision: high doses of thioridazinethioridazine

Copyright restrictions may apply.

Shah, G. K. et al. Arch Ophthalmol 1998;116:826-827.

Diffuse granular pigmentary retinopathy is evident in both the posterior pole (A and B) and periphery (C and D) of the right (A and C) and left (B and D) eyes


H.H. Cardiac ToxicityCardiac Toxicity• Thioridazine & mesoridazine: overdose Thioridazine & mesoridazine: overdose

associated with major ventricular associated with major ventricular arrhythmias, cardiac conduction block, and arrhythmias, cardiac conduction block, and sudden deathsudden death

• Patients should be given the usual "ABCD" Patients should be given the usual "ABCD" treatment for poisoningstreatment for poisonings


H.H. Cardiac ToxicityCardiac Toxicity• Ziprasidone carries the greatest risk of QT Ziprasidone carries the greatest risk of QT

prolongation and therefore should not be prolongation and therefore should not be combined with other drugs that prolong the combined with other drugs that prolong the QT interval, including thioridazine, pimozide, QT interval, including thioridazine, pimozide, and group 1A or 3 antiarrhythmic drugs and group 1A or 3 antiarrhythmic drugs

Drug InteractionsDrug Interactions

1)1) Pharmacodynamic interactionsPharmacodynamic interactions::• Additive/ potentiation effects with: Additive/ potentiation effects with:

a.a. Sedatives and analgesics, alcohol, & OTC Sedatives and analgesics, alcohol, & OTC sedatives and hypnotics, antihistamines, and sedatives and hypnotics, antihistamines, and cold remediescold remedies

b.b. α-adrenoceptor-blockersα-adrenoceptor-blockersc.c. Anticholinergics Anticholinergics d.d. Drugs with quinidine-like action (thioridazine)Drugs with quinidine-like action (thioridazine)


1)1) Pharmacodynamic interactionsPharmacodynamic interactions::• Antipsychotic Antipsychotic drugs inhibit the actions of drugs inhibit the actions of

dopaminergic agonists and levodopa and worsen dopaminergic agonists and levodopa and worsen the neurological symptoms of Parkinson’s diseasethe neurological symptoms of Parkinson’s disease

• The hypotensive effects of an antipsychotic may The hypotensive effects of an antipsychotic may be increased by diuretics, captopril, and other be increased by diuretics, captopril, and other antihypertensive medicationsantihypertensive medications


2)2) Pharmacokinetic interactions:Pharmacokinetic interactions:• Sedatives or anticonvulsants (e.g., Sedatives or anticonvulsants (e.g.,

carbamazepine, oxcarbazepine, phenobarbital, carbamazepine, oxcarbazepine, phenobarbital, and phenytoin) that induce CYPs can enhance and phenytoin) that induce CYPs can enhance the metabolism of antipsychoticthe metabolism of antipsychotic

• SSRIs (e.g. fluvoxamine, fluoxetine) compete for SSRIs (e.g. fluvoxamine, fluoxetine) compete for CYP450 enzymes and can elevate circulating CYP450 enzymes and can elevate circulating levels of antipsychotic drugslevels of antipsychotic drugs

chapter 29: antipsychotic agents. introduction the term psychosis refers to a variety of mental...

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