Antipsychotics Neuroleptics Psychosis and Schizophrenia The term psychosis

Antipsychotics (Neuroleptics)

Psychosis and Schizophrenia • The term “psychosis” denotes a variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not: the presence of delusions (false beliefs); various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory; and grossly disorganized thinking in a clear sensorium. • Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking and perceptual disturbance. It is the most common psychotic disorder, affecting about 1% of the population. • It is one of the most important forms of psychiatric illness, because it affects young people, is often chronic and is usually highly disabling. • Schizophrenia is considered to be a neurodevelopmental disorder. This implies that structural and functional changes in the brain are present even in utero in some patients, or that they develop during childhood and adolescence, or both. • Schizophrenia is a genetic disorder with high heritability. It involves common and rare mutations of multiple genes.

Clinical features of schizophrenia Positive symptoms • Delusions (often paranoid in nature). • Hallucinations (often in the form of voices). • Thought disorder • Abnormal, disorganized behaviour (such as stereotyped movements, disorientation and occasionally aggressive behaviours). • Catatonia (can be apparent as immobility or purposeless motor activity). Negative symptoms • Withdrawal from social contacts. • Flattening of emotional responses. • Anhedonia (an inability to experience pleasure). • Reluctance to perform everyday tasks. Cognition • Deficits in cognitive function (e. g. attention, memory).

Aetiology and pathogenesis of schizophrenia 1. Genetic and environmental factor: Although the causes of schizophrenia remain unclear but involve a combination of genetic and environmental factors. A person may have a genetic makeup that predisposes them to schizophrenia, but exposure to environmental factors may be required for schizophrenia to develop. 2. Neuroanatomical and neurochemical basis: Malfunctions in different neuronal circuits causes symptoms of schizophrenia. i. Positive symptoms of schizophrenia is associated with changes in the mesolimbic pathway (the neuronal projection from the ventral tegmental area (VTA) to the nucleus accumbens, amygdala and hippocampus) ii. Negative symptoms are associated with changes in the mesocortical pathway (the projection from the VTA to areas of the prefrontal cortex). 1. The main neurochemicals thought to be involved in the pathogenesis of schizophrenia are dopamine and glutamate. Although in the past, serotonin (5 -HT) has been shown to be implicated. Schizophrenia (SZP) is due to increased or dysregulated brain levels of monoamines, e. g. , dopamine (or 5 -HT) neurotransmission

Theories of schizophrenia The dopamine theory. • Patients on drugs that increase dopamine levels (e. g. , cocaine, amphetamine) or activate dopamine receptors (e. g. , apomorphine) present SZP-like symptoms, which subsides with decrease in drug levels • Dopamine receptor antagonists (especially D 2 antagonists) reduces SZP symptoms in many (NOT ALL) patients • Clinical improvement in SZP correlates with decreased dopamine levels in brain or decreased dopamine metabolites in blood • Levodopa therapy causes hallucinations as adverse effect The serotonin theory • Most 2 nd generation antipsychotics e. g. clozapine are inverse agonists of 5 HT 2 A receptors, i. e. they block the constitutive activity of these receptors. • They also have high affinity for other aminergic receptors, e. g. , α-adrenergic and histamine H 1 receptors

Theories of schizophrenia The glutamate theory • A number of studies have indicated that phencyclidine, ketamine, and other antagonists of the N-methyl-d-aspartate (NMDA) subtypes of glutamate receptors can cause schizophrenia-like symptoms (e. g. hallucinations, thought disorder) in healthy individuals and worsen symptoms in individuals with schizophrenia. • These findings have led to the glutamate hypothesis of schizophrenia. • Studies on post-mortem schizophrenic human brain tissues showed evidence of reduced glutamate receptor densities and glutamate concentration.

Antipsychotic drugs (Neuroleptics) Antipsychotics Phenothiazines Chlorpromazine Fluphenazine Typical Atypical or or 1 st Generation 2 nd Generation Butyrophenones Haloperidol Trifluperidol Thioxanthenes Flupenthixol Clozapine Olanzepine Risperidone Quetiapine

Mechanism of action of Antipsychotics Typical or 1 st Generation Atypical or 2 nd Generation • Bind to and block D 2 receptors at clinically-effective doses • Bind to and block D 2 and/or 5 -HT 2 A receptors at clinically-effective doses

Relative Binding Affinities of Some Antipsychotic Drugs for Various Receptors Compounds Dopamine D 1 Dopamine D 2 5 -HT 2 α 1 Adrenergic Muscarinic M 1 Histamine H 1 ++ +++ ++ + + +++ - ++ ± ++ +++ +++ +++ - + + + Typical Agents Chlorpromazine Fluphenazine Haloperidol Atypical Agents Clozapine Risperidone Ziprasidone

Pharmacological actions of antipsychotics 1. CNS: Effects differ in normal and psychotic individuals. Ø In normal individuals: chlorpromazine produces indifference to surroundings, paucity of thought, psychomotor slowing, emotional quietness, reduction in initiative and tendency to go off to sleep from which the subject is easily arousable (neuroleptic syndrome). Ø In a psychotic: chlorpromazine reduces irrational behaviour, agitation and aggressiveness and controls psychotic symptoms. Disturbed thought and behaviour are gradually normalized, anxiety is relieved. Hyperactivity, hallucinations and delusions are suppressed. • ANS: antipsychotics have varying degrees of α adrenergic blocking activity and weak anticholinergic property. The phenothiazines have weak H 1 -antihistaminic and anti-5 -HT actions as well. 1. Local anaesthetic: Chlorpromazine is a potent local anaesthetic agent, but because of its irritant action, it is not used for this purpose. 2. Cardiovascular: Neuroleptics produce hypotension

Adverse effects 1. CNS: Drowsiness, lethargy, mental confusion. Other side effects are increased appetite and weight gain (not with haloperidol); aggravation of seizures in epileptics; even nonepileptics may develop seizures with high doses of some antipsychotics like clozapine and occasionally olanzapine. 2. CVS: Postural hypotension, palpitation, inhibition of ejaculation are due to α adrenergic blockade; more common with low potency phenothiazines. 3. Anticholinergic : Dry mouth, blurring of vision, constipation, urinary hesitancy in elderly males 4. Endocrine : Hyperprolactinemia (due to D 2 blockade) is common with typical neuroleptics and risperidone. 5. Metabolic effects: Elevation of blood sugar and triglyceride levels 6. Extrapyramidal disturbances: Such as parkinsonism, Acute muscular dystonias (Bizarre muscle spasms, mostly involving linguo-facial muscles —grimacing, tongue thrusting, torticollis, locked jaw), Akathisia (Restlessness, feeling of discomfort, apparent agitation), Malignant neuroleptic syndrome and tardive dyskinesia. 7. Miscellaneous: Weight gain, blue pigmentation of exposed skin, eyes and retinal degeneration 8. Hypersensitivity reactions: Skin rashes, urticaria, contact dermatitis, Photosensitivity, etc