Antipsychotic and Antimanic Drugs

 Chapter 32 

Drugs Used in Mental Illness: Antipsychotic and Antimanic Drugs

• The psychopharmacological agents or psychotropic drugs are those having primary effects on psyche (mental processes) and are used for treatment of psychiatric disorders.

• During the past 50 years psychiatric treatment has witnessed major changes due to advent of drugs which can have specific salutary effect in mental illnesses. The trend has turned from custodial care towards restoring the individual patient to his place in the community. All that could be done before 1952 was to dope and quieten agitated and violent patients. The introduction of chlorpromazine (CPZ) in that year has transformed the lives of schizophrenics; most can now be rehabilitated to productive life. Reserpine was discovered soon after. Though it is a powerful pharmacological tool to study monoaminergic systems in brain and periphery, its clinical use in psychiatry lasted only few years. Next came the tricyclic and MAO inhibitor antidepressants in 1957–58 and covered another group of psychiatric patients. Many novel and atypical antipsychotics and antidepressants have been introduced since the 1980s. Meprobamate (1954) aroused the hope that anxiety could be tackled without producing marked sedation. This goal has been realized more completely by the development of Chlordiazepoxide (1957) and other benzodiazepines in the 1960s. Buspirone is a significant recent addition.

• Little attention was paid to Cade’s report in 1949 that Lithium could be used for excitement and mania: its effective use started in the 1960s and now it has a unique place in psychiatry. Interestingly some antiepileptics like carbamazepine, valproate and lamotrigine, etc. have shown promise in mania and bipolar disorders.

• Psychiatric diagnostic categories are often imprecise. The criteria adopted overlap in individual patients. Nevertheless, broad divisions have to be made, primarily on the basis of predominant manifestations, to guide the use of drugs. It is important to make an attempt to characterise the primary abnormality, because specific drugs are now available for most categories. Principal types are:

• Psychoses These are severe psychiatric illness with serious distortion of thought, behavior, capacity to recognize reality and of perception (delusions and hallucinations). There is inexplicable misperception and misevaluation; the patient is unable to meet the ordinary demands of life.

• Acute and chronic organic brain syndromes (cognitive disorders) Such as delirium and dementia; some toxic or pathological basis can often be defined; prominent features are confusion, disorientation, defective memory and disorganized behavior.

• Functional disorders No underlying cause can be defined; memory and orientation are mostly retained but emotion, thought, reasoning and behavior are seriously altered.

• Schizophrenia (split mind), i.e., splitting of perception and interpretation from reality—hallucinations, inability to think coherently.

• Paranoid states with marked persecutory or other kinds of fixed delusions (false beliefs) and loss of insight into the abnormality.    

• Affective disorders the primary symptom is change in mood state; may manifest as:    

• Mania—elation or irritable mood, reduced sleep, hyperactivity, uncontrollable thought and speech, may be associated with reckless or violent behavior, or

• Depression—sadness, loss of interest and pleasure, worthlessness, guilt, physical and mental slowing, melancholia, self-destructive ideation.

• It may be bipolar (manic-depressive) with cyclically alternating manic and depressive phases or unipolar (mania or depression) with waxing and waning course.

Neuroses These are less serious; ability to comprehend reality is not lost, though the patient may undergo extreme suffering. Depending on the predominant feature, it may be labelled as:

• Anxiety An unpleasant emotional state associated with uneasiness, worry, tension and concern for the future. 

• Phobic states Fear of the unknown or of some specific objects, person or situations. 

• Obsessive-compulsive Limited abnormality of thought or behavior; recurrent intrusive thoughts or ritual like behaviors which the patient realizes are abnormal or stupid but is not able to overcome even on voluntary effort. 

• Reactive depression due to physical illness, loss, blow to self-esteem or bereavement, but is excessive or disproportionate. 

• Post-traumatic stress disorder Varied symptoms following distressing experiences like war, riots, earthquakes, etc. 

• Hysterical Dramatic symptoms resembling serious physical illness, but situational, and always in the presence of others; the patient does not feign but actually undergoes the symptoms, though the basis is only psychic and not physical. Pathophysiology of mental illness is not clear, though some ideas have been formed, e.g., dopaminergic overactivity in the limbic system may be involved in schizophrenia and mania, while monoaminergic (NA, 5-HT) deficit may underlie depression. Treatment is empirical, symptom oriented and not disease specific. However, it is highly effective in many situations. Depending on the primary use, the psychotropic drugs may be grouped into:

 Antipsychotic

• (Neuroleptic, ataractic, major tranquillizer) useful in all types of functional psychosis, especially schizophrenia. (The term ‘Neuroleptic’ is applied to chlorpromazine/ haloperidol-like conventional antipsychotic drugs which have potent D2 receptor blocking activity and produce psychic indifference, emotional quietening with extrapyramidal symptoms, but without causing ataxia or cognitive impairment.)

Antimanic

• (Mood stabilizer) used to control mania and to break into cyclic affective disorders.

 Antidepressants

• used for minor as well as major depressive illness, phobic states, obsessive-compulsive behaviour, and certain anxiety disorders.

Antianxiety

• (Anxiolytic-sedative, minor tranquillizer) used for anxiety and phobic states. Antidepressants and antimanic drugs are sometimes collectively referred as ’Drugs for Affective Disorders’.

Psychotomimetic

• (Psychedelic, psychodysleptic, hallucinogen). These are seldom used therapeutically, but produce psychosis-like states; majority are drugs of abuse, e.g. cannabis, LSD.

• Tranquillizer It is an old term meaning “a drug which reduces mental tension and produces calmness without inducing sleep or depressing mental faculties.” It was used to describe the effects of reserpine or chlorpromazine. However, it has been interpreted differently by different people; some extend it to cover both chlorpromazine-like and antianxiety drugs, others feel that it should be restricted to the antianxiety drugs only. Their division into major and minor tranquillizers is not justified, because the ‘minor tranquillizers’ are not less important drugs: they are more frequently prescribed and carry higher abuse liability than the ‘major tranquillizers’. The term tranquillizer is, therefore, best avoided.

ANTIPSYCHOTIC DRUGS (Neuroleptics)

• These are drugs having a salutary therapeutic effect in psychoses

Phenothiazines

• Aliphatic side chain: Chlorpromazine Triflupromazine
• Piperidine side chain: Thioridazine
• Piperazine side chain: Trifluoperazine Fluphenazine 

• Many more drugs have been marketed in other countries but do not deserve special mention. Pharmacology of chlorpromazine (CPZ) is described as prototype; others only as they differ from it. Their comparative features are presented

PHARMACOLOGICAL ACTIONS

CNS Effects differ in normal and psychotic individuals

• In normal individuals CPZ produces indifference to surroundings, paucity of thought, psychomotor slowing, emotional quietening, reduction in initiative and tendency to go off to sleep from which the subject is easily arousable. Spontaneous movements are minimized but slurring of speech, ataxia or motor incoordination does not occur. This has been referred to as the ‘neuroleptic syndrome’ and is quite different from the sedative action of barbiturates and other similar drugs. The effects are appreciated as ‘neutral’ or ‘unpleasant’ by most normal individuals.

• In a psychotic CPZ reduces irrational behaviour, agitation and aggressiveness and controls psychotic symptomatology. Disturbed thought and behaviour are gradually normalized, anxiety is relieved. Hyperactivity, hallucinations and delusions are suppressed.

• All phenothiazines, thioxanthenes and butyrophenones have the same antipsychotic efficacy, but potency differs in terms of equieffective doses. The aliphatic and piperidine side chain phenothiazines (CPZ, triflupromazine, thioridazine) have low potency, produce more sedation and cause greater potentiation of hypnotics, opioids, etc. The sedative effect is produced promptly, while antipsychotic effect takes weeks to develop. Moreover, tolerance develops to the sedative but not to the antipsychotic effect. Thus, the two appear to be independent actions.

• Performance and intelligence are relatively unaffected, but vigilance is impaired. Extrapyramidal motor disturbances (see adverse effects) are intimately linked to the antipsychotic effect, but are more prominent in the high potency compounds and least in thioridazine, clozapine and other atypical antipsychotics. A predominance of lower frequency waves occurs in EEG and arousal response is dampened. However, no consistent effect on sleep architecture has been noted. The disturbed sleep pattern in a psychotic is normalized.

• Chlorpromazine lowers seizure threshold and can precipitate fits in untreated epileptics. The piperazine side chain compounds have a lower propensity for this action. Temperature control is knocked off at relatively higher doses rendering the individual poikilothermic—body temperature falls if surroundings are cold. The medullary respiratory and other vital centres are not affected, except at very high doses. It is very difficult to produce coma with these drugs. Neuroleptics, except thioridazine, have potenantiemetic action exerted through the CTZ. However, they are ineffective in motion sickness.

• In animals, neuroleptics selectively inhibit ‘conditioned avoidance response’ (CAR) without blocking the unconditioned response to a noxious stimulus. This action has shown good correlation with the antipsychotic potency of different compounds, though it may be based on a different facet of action. In animals, a state of rigidity and immobility (catalepsy) is produced which resembles the bradykinesia seen clinically.

Mechanism of action

• All antipsychotics (except clozapine-like atypical) have potent dopamine D2 receptor blocking action; antipsychotic potency has shown good correlation with their capacity to bind to D2 receptor. Phenothiazines and thioxanthenes also block D1, D3 and D4 receptors, but there is no correlation with antipsychotic potency. Blockade of dopaminergic projections to the temporal and prefrontal areas constituting the ‘limbic system’ and in mesocortical areas is probably responsible for the antipsychotic action. This along with the observation that drugs which increase DA activity (amphetamines, levodopa, bromocriptine) induce or exacerbate schizophrenia has given rise to the ‘Dopamine theory of Schizophrenia’ envisaging DA overactivity in limbic area to be responsible for the condition. As an adaptive change to blockade of D2 receptors, the firing of DA neurons and DA turnover increases initially. However, over a period of time this subsides and gives way to diminished activity, especially in the basal ganglia—corresponds to emergence of parkinsonian side effect. Tolerance to DA turnover enhancing effect of antipsychotics is not prominent in the limbic area—may account for the continued antipsychotic effect.

• The above model fails to explain the antipsychotic activity of clozapine and other atypical antipsychotics which have weak D2 blocking action. However, they have significant 5-HT2 and α1 blocking action, and some are relatively selective for D4 receptors. Thus, antipsychotic property may depend on a specific profile of action of the drugs on several neurotransmitter receptors. Recent positron emission tomography (PET) studies of D2 and other receptor occupancy in brains of antipsychotic treated patients have strengthened this concept.

• Dopaminergic blockade in the basal ganglia appears to cause the extrapyramidal symptoms, while that in CTZ is responsible for antiemetic action

ANS 

• Neuroleptics have varying degrees of α adrenergic blocking activity which may be graded as:

• CPZ = triflupromazine > thioridazine > clozapine > fluphenazine > haloperidol > trifluoperazine > pimozide, i.e. more potent compounds have lesser α blocking activity

• Anticholinergic property of neuroleptics is weak and may be graded as:

• thioridazine > CPZ > triflupromazine > trifluoperazine = haloperidol.

• The phenothiazines have weak H1-antihistaminic and anti-5-HT actions as well.

 Local anaesthetic

• Chlorpromazine is as potent a local anaesthetic as procaine. However, it is not used for this purpose because of its irritant action. Others have weaker membrane stabilizing action.

CVS 

• Neuroleptics produce hypotension (primarily postural) by a central as well as peripheral action on sympathetic tone. The hypotensive action is more marked after parenteral administration and roughly parallels the α adrenergic blocking potency. Hypotension is not prominent in psychotic patients but is accentuated by hypovolemia. Partial tolerance develops after chronic use. Reflex tachycardia accompanies hypotension.

• High doses of CPZ directly depress the heart and produce ECG changes (Q-T prolongation and suppression of T wave). CPZ exerts some antiarrhythmic action, probably due to membrane stabilization. Arrhythmia may occur in overdose, especially with thioridazine.

Skeletal muscle 

• Neuroleptics have no effect on muscle fibres or neuromuscular transmission. They reduce certain types of spasticity: the site of action being in the basal ganglia or.