Chapter 29: Antipsychotic Agents & Lithium

1. Chapter 29:Antipsychotic Agents & Lithium

2. Introduction • The term psychosis refers to a variety of mental disorders characterized by one or more of the following symptoms: • Diminished and distorted capacity to process information and draw logical conclusions • Hallucinations, usually auditory or visual, but sometimes tactile or olfactory • Delusions (false believes) • Incoherence or marked loosening of associations • Catatonic or disorganized behavior • Aggression or violence

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

4. Nature of Psychosis & Schizophrenia • Schizophrenia is a particular type of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance • Because it affects young people, is often chronic and is usually highly disabling • There is a strong hereditary factor in its aetiology, and evidence suggestive of a fundamental biological disorder (neurodevelopmental disorder)

5. Nature of Psychosis & Schizophrenia • The main clinical features of the disease are: • Positive symptoms: • Delusions (often paranoid in nature) • Hallucinations, usually in the form of voices which are often exhortatory in their message • Thought disorder, comprising wild trains of thought, garbled sentences and irrational conclusions, sometimes associated with the feeling that thoughts are inserted or withdrawn by an outside agency • Abnormal behaviours, such as stereotyped movements and occasionally aggressive behaviours • Negative symptoms: • Withdrawal from social contacts • Flattening of emotional responses • Lack of motivation

6. Nature of Psychosis & Schizophrenia • The clinical phenotype varies greatly, particularly with respect to the balance between negative and positive symptoms • The pathogenesis of schizophrenia is unknown • Pharmacological evidence is consistent with DA hyperactivity hypothesis. There is also evidence of glutamate & 5-HT involvement • Schizophrenia has familial incidence

7. Neurochemical theories • Came mainly from analyzing the effects of antipsychotic and propsychotic drugs-from pharmacology rather than from neurochemistry • The main neurochemical theories centre on dopamine and glutamate, although other mediators, particularly 5-HT, are also receiving attention

8. Neurochemical theories • The Dopamine theory of schizophrenia • It is based on multiple lines of evidence suggesting that excessive dopaminergic activity underlies schizophrenia • It is still highly relevant to understanding the major dimensions of schizophrenia, such as positive and negative symptoms, cognitive impairment, and possibly depression

9. Neurochemical theories • The Dopamine theory of schizophrenia • It is also essential to understanding the MOA of most and probably all antipsychotic drugs • However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia, especially the cognitive impairment

10. The Serotonin Hypothesis of Schizophrenia • The Serotonin theory of schizophrenia • It has been found that 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine • 5-HT2A-receptors modulate the release of dopamine, norepinephrine, glutamate, GABA and acetylcholine in the cortex, limbic region, and striatum

11. Neurochemical theories • The Glutamate theory of schizophrenia • Glutamate is the major excitatory neurotransmitter in the brain • Phencyclidine and ketamine are noncompetitive inhibitors of the N-methyl-D-aspartate (NMDA) receptor can exacerbate both cognitive impairment and psychosis in patients with schizophrenia • Hypofunction of NMDA receptors, located on GABAergic interneurons contributed to schizophrenia

12. Antipsychotic Agents • Are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, senile psychoses, various organic psychoses, and drug-induced psychoses • They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients

13. Antipsychotic Agents • Their antipsychotic actions appear to reflect a blockade at dopamine and/or serotonin receptors • Many of these agents also block cholinergic, adrenergic, and histaminergic receptors. The undesirable side effects of these agents are often a result of actions at these other receptors

14. Antipsychotic Agents Atypical antipsychotic drugs Loxapine Clozapine* Asenapine Olanzapine Quetiapine PaliperidoneRisperidone Sertindole ZiprasidoneZotepine Aripiprazole Typical antipsychotic Drugs a) Low Potency Chlorpromazine Thioridazine Thiothixene Prochlorperazine b) High potency Haloperidol Pimozide Molindone Fluphenazine

15. Dopaminergic Systems • Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs: • Mesolimbic-mesocortical pathway: the one most closely related to behavior and psychosis • Nigrostriatal pathway: it is involved in the coordination of voluntary movement. Blockade of the D2 receptors in the nigrostriatal pathway is responsible for EPS

16. Dopaminergic Systems • Tuberoinfundibular system: it releases dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary • Medullary-periventricular pathway: it may be involved in eating behavior • Incertohypothalamic pathway: It appears to regulate the anticipatory motivational phase of copulatorybehavior in rats

17. Mechanism of action • Typical antipsychotic agents • The clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain • The binding affinity of the typical is very strongly correlated with clinical antipsychotic and extrapyramidal potency: the typical antipsychotic drugs must be given in sufficient doses to achieve 60% occupancy of striatal D2 receptors

18. Mechanism of action • Typical antipsychotic agents • These drugs vary in potency: chlorpromazine is a low-potency drug, and fluphenazine is a high-potency agent • No one drug is clinically more effective than another

19. Mechanism of action • Typical antipsychotic agents • Antagonism of the of dopamine in the nigrostriatal system is the major factor in the extrapyramidal side effects (EPS) seen with these agents • EPS are produced when the occupancy of striatal D2 receptors reaches 80% or higher • Antagonism of dopamine’s neurohormonal action in the anterior pituitary accounts for the hyperprolactinemia associated with antipsychotic administration

20. Mechanism of action • Atypical antipsychotic drugs • These drugs have complex pharmacology but they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor action • They do not have very high affinity for the D2 receptor: effective at lower occupancy levels of the dopamine receptors (30–50%) • The posses high occupancy of 5-HT2A receptors • As a result, they have fewer extrapyramidal adverse effects than the older, traditional agents

21. Mechanism of action • Atypical antipsychotic drugs • Atypical antipsychotic drugs are inverse agonists of the 5-HT2A receptor; that is, they block the constitutive activity of these receptors • In most cases, they act as partial agonists at the 5-HT1A receptor, which produces synegistic effects with 5-HT2A receptor antagonism

22. Differences among Antipsychotic Drugs • All effective antipsychotic drugs block D2 receptors, the degree of this blockade in relation to other actions on receptors varies considerably among drugs • Most of the newer atypical agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors • The antipsychotics also have variable antagonist actions at muscarinic, α-adrenergic, and histaminergic receptors in brain and peripheral tissue

25. Clinical Uses • Psychiatric Indications (schizophrenia) • The principal goals for the management of a chronic schizophrenic disorder are the minimizing of symptoms and the prevention of exacerbations • All of the antipsychotic drugs can reduce the hallucinations and delusions (positive symptoms) associated with by blocking dopamine receptors in the mesolimbic system of the brain • No one drug or combination of drugs selectively affects a particular symptom complex

26. Clinical Uses • Psychiatric Indications (schizophrenia) • For approximately 70% of patients with schizophrenia typical and atypical antipsychotic drugs are of equal efficacy for treating positive symptoms • Atypical drugs ameliorate the negative symptoms and cognition, diminished risk of tardive dyskinesia and other forms of EPS, and are favored for lesser increases in prolactin levels

27. Clinical Uses • Psychiatric Indications (schizophrenia) • Drug choice is determined mainly by the patient’s past responses and the drug’s potential for producing adverse effects • The clinical trend is to prescribe the higher-potency atypical agents

28. Clinical Uses • Psychiatric Indications (schizophrenia) • Other indications for the use of antipsychotics include: • Tourette's syndrome • Disturbed behavior in patients with Alzheimer's disease • Psychotic depression (with antidepressants)

29. Clinical uses B. Nonpsychiatric Indications • Antiemetics • Prochlorperazine & benzquinamide are useful in the treatment of drug-induced nausea • This action is due to DA receptor blockade, both centrally (in chemoreceptor trigger zone of the medulla) & peripherally (on receptors in the stomach) • The atypical antipsychotic drugs are not used as antiemetics

30. Clinical uses B. Nonpsychiatric Indications • Antipruritic: some phenothiazines with considerable H1 receptor-blocking action e.gprochlorperazine • Preoperative sedation (promethazine) • Neuroleptanesthesia (droperidol)

31. Adverse reactions • Antipsychotic drugs are characterized by high therapeutic indices with respect to mortality, but side effects occur routinely at therapeutic doses, mostly as extensions of pharmacological actions • The characteristic neurological symptoms caused by these agents are particularly troublesome, often limit the tolerated dose, and may interfere with the desired benefits and patient compliance

32. Adverse Reactions • Behavioral Effects • The older typical antipsychotic drugs are unpleasant to take • Many patients may experience "pseudodepression" due to drug-induced akinesia usually responds to treatment with antiparkinsonism drugs • Pseudodepressions may be due to higher doses than needed in a partially remitted patient, in which case decreasing the dose may relieve the symptoms • Toxic-confusional states with very high doses of drugs that have prominent antimuscarinic actions

33. Adverse Reactions • Extrapyramidal side effects (EPS) • The inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons in the striatum • Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence, which results in extrapyramidal motor effect • Two extrapyramidal conditions, acute dystonic reactions (spastic retrocollis or torticollis) and akathisia (uncontrollable restlessness), occur early during treatment, while parkinsonism tends to evolve gradually over days to weeks

35. Adverse Reactions • Extrapyramidal side effects (EPS) • Occur most commonly with the high-potency typical antipsychotics (e.g. haloperidol and fluphenazine) • Drugs that exhibit strong anticholinergic activity, such as thioridazine (low-potency typical), show fewer EPS, because the cholinergic activity is strongly dampened

36. Adverse Reactions • Extrapyramidal side effects (EPS) • Atypical antipsychotics (clozapine and risperidone) exhibit a lower potential for causing extrapyramidal symptoms, which has been attributed to their blockade of 5-HT2A receptors

37. Adverse Reactions B. Extrapyramidal side effects (EPS) • Parkinsonism can be treated with antimuscarinic drugs (e.g. benzotropine), or amantadine. (Levodopa should never be used in these patients) • Akathisia and dystonic reactions preferably treated with a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orally

39. Adverse Reactions • Tardive dyskinesia • The most important unwanted effect of antipsychotic drugs • Develops after months or years in 20-40% of patients treated with first-generation antipsychotic drugs • Patients display involuntary movements, including lateral jaw movements and “fly-catching”‌ motions of the tongue

41. Adverse Reactions • Tardive dyskinesia • Its seriousness lies in the fact that it is a disabling and often irreversible condition • It is caused by relative cholinergic deficiency secondary to supersensitivity of DA receptors in the caudate-putamen (D2-receptor up-regulation?) • Appropriately managed by reducing the dose or to switch to one of the newer atypical agents (quetiapine or clozapine, the atypical agents with the least likelihood of causing tardive dyskinesia)

42. Adverse Reactions • Neurologic Effects • Neuroleptic malignant syndrome is a rare medical emergency occurs in patients who are extremely sensitive to the EPS of antipsychotic agents • It occurs in about 1% of patients receiving antipsychotic and about 10% of these cases are fatal • It is characterized by muscle rigidity, fever as a result of sweating impairment, altered mental status and stupor, unstable blood pressure, and myoglobinemia

43. Adverse Reactions • Neurologic Effects • Muscle-type creatine kinase levels are usually elevated, reflecting muscle damage • This syndrome is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors • Treatment necessitates discontinuation of the antipsychoyic drug and supportive therapy

44. Adverse Reactions C. Autonomic Nervous System Effects • Antipsychotics have variable antagonistic interactions at peripheral adrenergic, cholinergic, and histsmine receptors; thus, the drugs’ effects on the ANS are complex and unpredictable • α-adrenergic-blocking actions (chlorpromazine, mesoridazine): orthostatic hypotension or impaired ejaculation

45. Adverse Reactions C. Autonomic Nervous System Effects • Antimuscarinic effects (thioridazine, chlorpromazine, clozapine, and olanzapine): blurred vision, dry mouth (exception: clozapine increase salivation), confusion, constipation, and urinary retention

46. Adverse Reactions • Toxic or Allergic Reactions: • Agranulocytosis: clozapine in ~1-2%. • Because of the risk, weekly blood counts are mandatory for patients receiving clozapine for the first 6 months of treatment and every 3 weeks thereafter • Cholestatic jaundice • Urticarial skin reactions (common but usually mild)

47. Adverse Reactions • Metabolic & Endocrine Effects • Weight gain, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates • Hyperglycemia secondary to weight gain-associated insulin resistance • Hyperlipidemia

48. Adverse Reactions • Metabolic & Endocrine Effects • Endocrine changes occur because of effects of antipsychotic drugs on the hypothalamus or pituitary, including their antidopaminergic actions • In the pituitary, older typical antipsychotic drugs, as well as risperidone and paliperidone, block D2 receptors, leading to an increase in prolactin release

49. Adverse Reactions • Metabolic & Endocrine Effects • Atypical neuroleptics are less likely to produce prolactin elevations because their diminished D2 antagonism • Amenorrhea and increased libido have been reported in women, whereas decreased libido and gynecomastia have been observed in men

50. Adverse Reactions • Ocular Complications: • Opacities of the cornea and lens: due to deposition the anterior portions of the eye are a common complication of chlorpromazine therapy • Pigmentary retinopathy associated with "browning" of vision: high doses of thioridazine