The central nervous system comprises the brain, spinal cord and peripheral nerves (Fig. 14.1). There is a vast number of nerves, each consisting of a nerve cell otherwise termed a neurone and its processes, axons and dendrites. The neurones conduct nerve impulses that are akin to tiny electrical charges. Axons, which are usually longer than dendrites, carry nerve impulses away from the cell. Large axons are surrounded by a myelin sheath. Dendrites are nerve fibres that carry impulses towards nerve cells. They form synapses with dendrites of other neurones or terminate in specialised sensory receptors such as those in the skin.

Fig. 14.1 The brain.

(From Waugh A, Grant A 2001. Ross and Wilson anatomy and physiology in health and illness, 9th edn. Churchill Livingstone, Edinburgh. With permission of Elsevier.)

SYNAPSE AND CHEMICAL TRANSMITTERS

A synapse is where nerve impulses are transmitted from one neurone, called the presynaptic neurone, to another neurone, called the postsynaptic neurone. The space between them is the synaptic cleft. Chemical transmitters carry nerve impulses across the synaptic cleft (Fig. 14.2). Noradrenaline (norepinephrine), gamma-aminobutyric acid (GABA), acetylcholine, dopamine and serotonin (5-hydroxytryptamine) are examples of chemicals that act as transmitters. The endings of autonomic nerves supplying smooth muscle and glands release a transmitter substance that stimulates or depresses the activity of the structure.

Fig. 14.2 Synaptic cleft.

(From Waugh A, Grant A 2001. Ross and Wilson anatomy and physiology in health and illness, 9th edn. Churchill Livingstone, Edinburgh. With permission of Elsevier.)

THE BRAIN

The parts comprising the brain are the:

The peripheral part of the cerebrum is composed of nerve cells or grey matter forming the cerebral cortex, and the deeper layers consist of nerve fibres or white matter. The types of activity associated with the cerebral cortex are:

• mental activities – memory, reasoning, learning

• sensory perception – pain, temperature, touch, sight, hearing, taste, smell

• control of voluntary muscle contraction.

The midbrain consists of nerve cells and fibres con-necting the cerebrum with lower parts of the brain and with the spinal cord. The medulla oblongata extends from the pons varolii and is continuous with the spinal cord. The vital centres, comprising groups of cells associated with the autonomic reflex activity, lie within the medulla oblongata; they are listed in Table 14.1.

Table 14.1 The vital centres of the brain

Centre	Effect of stimulation
Cardiac centre	Sympathetic stimulation increases the rate and force of the heartbeat; parasympathetic stimulation has the opposite effect
Respiratory centre	Controls rate and depth of respiration
Vasomotor centre	Controls diameter of blood vessels; the vasomotor centre may be stimulated by baroreceptors, body temperature, emotion
Reflex centre	Irritating substances in the stomach or respiratory tract cause nerve impulses to pass to the medulla oblongata, which initiate reflex actions such as vomiting, coughing or sneezing

The cerebellum coordinates voluntary muscle movement, posture and balance. The sensory input is derived from the muscles, joints, eyes and ears. Damage to the cerebellum results in uncoordinated muscular movement such as staggering gait.

COMMON DISORDERS

INSOMNIA

Normal sleep is of two kinds.

• Slow wave sleep (SWS):

— heart rate, blood pressure, respiration are steady or in decline

— muscles are relaxed

— growth hormone secretion is maximal.

• Rapid eye movement (REM):

— heart rate, blood pressure, respiration fluctuate

— cerebral blood flow increases above that during wakefulness

— skeletal muscles are profoundly relaxed, although body movements are more pronounced (dreaming sleep).

A ‘normal’ night consists of a sleep latency period that varies from person to person (the ‘dropping off’ stage), followed by SWS sleep for about 1 h, REM sleep for about 20 min, SWS for approximately 90 min and REM sleep for about 20 min, and the rest of the night alternates between SWS and REM sleep until wakefulness. Both kinds of sleep appear necessary for normal health.

Insomnia affects most of us at some time in our lives. For the majority it is transient, but for some people insomnia becomes a chronic problem. Many people who sleep badly complain of tiredness during the day and mood disturbance. Insomnia may be characterised by:

• difficulty in falling asleep

• difficulty in staying asleep

• short unrefreshing sleep.

However, individual requirements differ, some people finding that only 4–6 h is adequate, whereas others require 8 or 9 h to feel refreshed the following day. In general, the elderly require less sleep than the young.

Hypnotics are often prescribed without adequate clinical evaluation to recognise underlying emotional or physical causes that may respond to specific psychotherapy or pharmacotherapy.

When insomnia is caused by the following symptoms, treatment of these primary symptoms may relieve the problem: pain, dyspnoea, cough, frequency of micturition, excita tory drugs (e.g. caffeine), pruritus.

Insomnia is a common feature of psychiatric illness, particularly in anxiety states and depressive illness. Difficulty in getting to sleep is found in both depression and anxiety, and early morning awakening is common in depression. Choosing a medication to treat the illness with a secondary hypnotic activity can assist in alleviating the insomnia. For example, in depressed patients with early wakening a sedative antidepressant (e.g. mirtazapine) may be sufficient.

Certain drugs may produce insomnia, particularly the methylxanthines (theophylline and caffeine), the amphetamines and selegiline. Sleep disturbance is likely to be experienced in the early stages of treatment, and medication may need to be reviewed if problems persist.

Three main types of insomnia have been identified according to their duration.

• Transient insomnia. This may occur in those who normally sleep well, due to factors such as jet lag, shift work or acute stress, and lasts for only a few days. Only one or two doses of a hypnotic should be given.

• Short-term insomnia. This is usually related to an emotional problem such as bereavement, problems at work or marital relations. A hypnotic should not be given for more than 3 weeks (preferably only 1 week), omitting doses when not required.

• Long-term (chronic) insomnia. This can have many causes. Prescription of hypnotics in long-term insomnia is rarely beneficial.

NON-DRUG TREATMENT

A regular bedtime routine helps to induce sleep. Warm, milky drinks (not tea or coffee) can help. Relaxation exercises or relaxing with a book may be beneficial. An equable environmental temperature will be conducive to sleep.

DRUG TREATMENT

Table 14.2 indicates the half-lives and dosages of commonly used hypnotics.

Table 14.2 Half-lives and dosages of hypnotics ^a

Drug	Elimination half-life (h)	Hypnotic dose (mg)
Benzodiazepines
Loprazolam	6–12	0.5–2
Lormetazepam	10–12	0.5–1.5
Temazepam	8–15	10–40
Non-benzodiazepines
Zaleplan	1	5–10
Zolpidem	2.5–3	5–10
Zopiclone	5–8	3.75–7.5

a Doses are adult doses. Dosage should be reduced in older people.

SUMMARY

The ideal hypnotic does not exist, and hypnotics should be reserved for people whose insomnia is debilitating. They should be prescribed for short courses and only when all underlying causes of insomnia have been investigated and treated.

ANXIETY

Anxiety is a normal reaction we all experience when faced with major events in our lives such as moving house and attending interviews. It becomes a medical problem only when it is excessive or inappropriate. The patient may describe a sensation of fear or dread, varying from mild to an overwhelming feeling of terror, the latter leading to panic attacks.

Physical symptoms include tremor, tensing of muscles, perspiration (particularly of the hands and forehead), hypertension, palpitations, gastrointestinal disturbances (such as frequency of defaecation), back pain, chest pain, dizziness and dyspnoea. These symptoms are very marked in panic attacks.

TREATMENT

Treatment of anxiety includes psychotherapy (relaxation, behavioural and reassurance techniques) as well as drug therapy. The decision whether to use psychotherapy, drug therapy or a combination of both is determined by the practitioner.

Drug treatment should be limited to the lowest possible dose for the shortest possible time. It relies mainly on the use of anxiolytics such as benzodiazepines and buspirone, but beta-blockers, antidepressants with a sedative action (such as clomipramine) and antipsychotics (such as zuclopenthixol) have also been used with varying degrees of success.

BENZODIAZEPINES

Benzodiazepines are anxiolytic, sedative and, in large doses, hypnotic. They also show muscle relaxant and anticonvulsant properties.

Benzodiazepines potentiate the effects of GABA, the major inhibitory transmitter in the brain, by binding with the receptor complex.

Pharmacokinetics.

Compounds with a high potency at the receptor site and with a long half-life are best suited for use in anxiety, as they are less likely to cause withdrawal problems. For this reason, diazepam is suitable, with a half-life of 14–17 h and active metabolites. It is rapidly absorbed and quick-acting.

Chlordiazepoxide is also a long-acting benzo-diazepine, and this type is most useful when a sustained action is required. Short-acting benzodiazepines (lorazepam, oxazepam) are used in intermittent anxiety such as episodes of panic, phobic disorders and acute stressful situations (e.g. public speaking, when a briefer action is required).

Table 14.3 gives dose ranges of benzodiazepines.

Table 14.3 Dose ranges of some benzodiazepines

Drug	Dose
Chlordiazepoxide	10 mg three times daily, increased if necessary to 60–100 mg daily in divided doses
Diazepam	2 mg three times daily, increased if necessary to 15–30 mg daily in divided doses
Lorazepam	1–4 mg daily in divided doses
Oxazepam	15–30 mg three or four times daily

Reduced doses should be used in the elderly and in hepatic impairment.

Side effects.

Benzodiazepines are generally well tolerated. However, sedation, ataxia, confusion, amnesia and dependence may occur.

BETA-BLOCKERS

Beta-blockers (e.g. propranolol, oxprenolol; see p. 200) do not affect psychological symptoms such as fear, worry and tension. They do, however, reduce autonomic symptoms such as palpitations and tremor.

BUSPIRONE

Buspirone has anxiolytic effects but lacks sedative, anticonvulsant and muscle relaxant properties. Buspirone is rapidly absorbed and undergoes considerable first-pass metabolism. It is eliminated by the liver and has a half-life of 2–11 h. Its anxiolytic effect occurs after 2 weeks of continuous therapy.

Initially, the dose is 5 mg two or three times daily, increased as necessary every 2–3 days; usual range 15–30 mg daily in divided doses; maximum 45 mg daily.

Side-effects.

Common side-effects include drowsiness, dizziness, headache, lightheadedness, excitement and nausea, which occur most commonly at the beginning of treatment. No withdrawal symptoms have been reported on stopping treatment after 6 weeks to 6 months, and there is no evidence of tolerance. Buspirone does not appear to have an additive effect with alcohol. Diazepam remains the drug of choice for treatment of anxiety.

PSYCHOSES

Antipsychotic drugs, also known as neuroleptics, are used in the symptomatic treatment of psychoses, including schizophrenia and the manic phase of manic depressive illness. Antipsychotics can also be used to calm children with learning difficulties and agitated elderly patients.

SCHIZOPHRENIA

Schizophrenia is a severe mental illness affecting 1% of the population at some time in life. It can have a profound effect on a person’s reasoning and thought processes, emotions and behaviour. Most people with schizophrenia are unable to hold down a job, have few friends and find it difficult to interact socially.

Schizophrenia can develop at any age but most commonly manifests itself in the late teens or early twenties. It affects both sexes equally, but women have a slightly later average age of onset. About 250 000 people are suffering from schizophrenia in Britain today, and each year about 35 000 patients with the condition are admitted to hospital. It involves the most basic attributes that give people a sense of individuality, uniqueness and direction in life. It causes a disintegration of the personality, with a wide range of symptoms and abnormal behaviour. These include delusions, often of persecution, hallucinations, usually of accusatory or abusive voices, incoherence of speech and thought, abnormal movements and a flattened affect. Hallucinations can, however, involve all senses including olfactory, tactile, visual and taste. During the illness, functioning at work, family life, social relations and self-care may deteriorate markedly. The symptoms are divided into two classes.

• Positive symptoms such as hallucinations, delusions and thought disorders.

• Negative symptoms, including marked social isolation or withdrawal, lack of volition, poverty of speech, anhedonia, failure in role functioning as wage earner or homemaker and marked lack of interests, motivation and energy. Some patients are predominantly disorganised in their behaviour and others mainly paranoid. The negative symptoms are often more prominent during the later stages of the illness, hampering rehabilitation and discharge into the community.

The disease frequently creates heavy burdens for the sufferer, often throughout the person’s adult life. Furthermore, there is likely to be considerable impact on the patient’s family and on society. The course of the illness varies. About 25% of people who present recover fully within a few months; another 50% recover but suffer recurring episodes of illness throughout their life. The remaining 25% are permanently disabled and provide the bulk of management problems and require constant intensive treatment. Table 14.4 provides prognostic indicators.

Table 14.4 Prognostic indicators in schizophrenia

Good	Bad
No family history	Family history
Good premorbid personality	Shy, solitary
Functions well in work environment	Poor work record
Precipitating cause	No precipitating cause
Acute onset	Gradual onset
Prompt treatment	Delayed treatment

DRUG TREATMENT

The aim is to treat both positive and negative symp-toms and to increase social functioning. Consent must be obtained for treatment unless there is a risk of significant harm to the patient or others by virtue of non-treatment of the illness, at which point the mental health legislation may require to be invoked to enable the patient to receive the appropriate treatment. Compulsory admission to hospital for treatment can be applied for under the terms of the relevant sections of the Mental Health (Care and Treatment) Acts if there is a significant risk of patients harming themselves or others as a result of their mental illness.

Conditions for compulsory detention and/or treatment orders are specified in the relevant Mental Health Acts. Patients retain the right of appeal against the imposition of such orders, and they are also protected by the involvement of the Mental Welfare Commission, the appointment of a mental welfare officer (usually a specially trained social worker) and the requirement to identify a named person to represent their interests.

The choice of drug treatment should be discussed with the multidisciplinary team. The choice of antipsychotic drug and the route of administration will depend on the individual circumstances of the patient. The dose will require to be titrated against clinical symptoms and side effects. Counselling and discussion with the patient of anticipated effects and side effects will create a better understanding, resulting in improved compliance and an increased likelihood of a positive outcome.

Mechanism of action of antipsychotic drugs.

The mechanism of action is complex, and many details remain to be established. However, psychotic symptoms result from overactivity of the dopaminergic system. Antipsychotic drugs are believed to act by blocking dopamine receptors, especially D₂-dopaminergic receptors in the brain and, in this way, counterbalance the overactive dopaminergic system. While this will result in an antipsychotic effect, depending on the ability of the drugs to block the dopamine receptors, there may be extrapyramidal side-effects and parkinsonian symptoms.

The antipsychotics may block other central neuro-transmitter pathways, and this may be clinically relevant.

• Cholinergic blockade is associated with dry mouth, blurred vision, constipation and urinary retention. Antipsychotic drugs with a significant antimuscarinic effect should not therefore be administered to patients with angle closure glaucoma or prostatism.

• Alpha-adrenergic blockade is associated with postural hypotension, particularly in the elderly.

• Histamine receptor blockade is associated with sedation, which may be desirable in some patients but not in others.

Pharmacokinetics.

Oral antipsychotics generally show unpredictable absorption. Drug availability may be increased 4–10 times on intramuscular administration. Most antipsychotics have long elimination half-lives of about 20–40 h, which allow once-a-day dosage after stabilisation of the patient’s condition. Older patients have a reduced capacity to metabolise and eliminate these drugs.

Administration of medication.

The dose of anti-psychotic drugs must be individualised for each patient with respect to severity of illness, drug potency, route of administration, age, weight and liver function. A key factor is to ensure that the dose of medication is kept as low as possible. Treatment is usually initiated at low dose and increased gradually until symptom control is achieved or until side-effects limit further increases. Very large doses rarely improve response and usually increase the burden of side-effects. Because of slower metabolism and elimination rate, older people require much smaller doses.

Three main factors influence the choice of anti-psychotic medication:

• previous good response to an individual drug would point to use of the same drug on a subsequent occasion, and vice versa

• severity of the illness and the predominant symptoms

• side-effect profile.

Side-effects.

Antipsychotics have a wide range of side effects, the severity varying between different groups and between individual drugs. These are grouped as follows.

• Autonomic nervous system (anticholinergic):

Particular care is required in older people, because of the possibility of precipitating urinary retention or adversely affecting glaucoma. Postural hypotension associated with alpha-adrenergic blockade may also be troublesome in the elderly.

• Metabolic/endocrine:

— weight gain

— hyperprolactinaemia

— galactorrhoea

— gynaecomastia

— amenorrhoea

— hypo- or hyperthermia.

Neuroendocrine effects, which include gynaecomastia, galactorrhoea and amenorrhoea, occur less frequently. They are a consequence of a rise in prolactin (hyper-prolactinaemia) following dopamine blockade of the pituitary gland.

• Allergic/toxic:

— cardiac arrhythmias

— neuroleptic malignant syndrome

— jaundice (chlorpromazine)

— dermatitis

— photosensitivity

— blood dyscrasias.

All antipsychotic medications have the potential to cause blood dyscrasias. Clozapine has a much greater potential to cause agranulocytosis. Neuroleptic malignant syndrome is thought to occur in 0.5% of newly treated patients and to be greatly underdiagnosed. It is a potentially life-threatening complication of neuroleptic treatment. The main symptoms are hyperthermia, fluctuating consciousness, muscular rigidity, autonomic disturbance and extrapyramidal symptoms. The risk is greater the higher the starting dose of antipsychotic and the more rapidly it is increased. Antipsychotic symptomatic treatment should be stopped while the drug washes out. Intensive medical treatment is required when bromocriptine (a dopaminergic agonist) and dantrolene (a skeletal muscle relaxant) are usually administered.

• Central nervous system:

— sedation

— reduced convulsive threshold

— extrapyramidal side effects.

Sedation may be useful when a patient is agitated. Antipsychotics lower the seizure threshold in a dose-dependent manner. The more potent, less sedative drugs tend to carry a greater risk than the less potent, more sedative drugs. Clozapine carries the greatest risk.

Extrapyramidal side-effects.

Extrapyramidal reactions are well-recognised complications of antipsychotic medication. Clinical features are acute dystonia, akathisia, tardive dyskinesia and parkinsonism.

ACUTE DYSTONIA

Acute dystonias most commonly affect children and young adults. These frightening and sometimes painful conditions affect mainly the muscles of the face, jaw, neck and trunk. Typically, patients present with torticollis, facial grimacing and oculogyric spasm. Dystonias usually occur within 1–2 days of starting antipsychotic treatment but may also develop on drug withdrawal. Occasionally, persistent dystonias develop during prolonged treatment with antipsychotic drugs. Acute and subacute reactions will often improve or resolve rapidly on drug withdrawal. When this is not possible, reducing the dose of the drug or switching to another drug may improve symptoms. Acute dystonic reactions are treated with an antimuscarinic drug (e.g. procyclidine) given parenterally and continued by mouth, or with a benzodiazepine (e.g. diazepam).

AKATHISIA

This is characterised by restlessness and unease, which may be intense and distressing. Patients typically describe an inability to keep their legs still and feel a compulsion to move about. Akathisia usually occurs soon after starting drug therapy or after a rapid increase in dose. Persistent akathisia can develop in patients on long-term treatment with antipsychotics. Acute akathisia only rarely responds to treatment with antimuscarinic drugs, and these may exacerbate the problem, but a low dose of a beta-blocker or benzodiazepine may be helpful.

TARDIVE DYSKINESIA

This is most commonly seen in patients on chronic antipsychotic medication. It develops after months or years of treatment and is characterised by abnormal involuntary movements of the face (e.g. lip smacking, lateral jaw movements, fly-catching movements of the tongue) or trunk (e.g. rocking). Increasing age appears to be a risk factor. Withdrawal of long-term antipsychotics may unmask tardive dyskinesia. Symptoms may persist for an indefinite period after the drug has been discontinued. Concomitant administration of antimuscarinic drugs can worsen tardive dyskinesia, and these should be stopped if this can be done without precipitating severe parkinsonism. There is, however, no convincing evidence to support the idea that long-term antimuscarinics increase the risk of tardive dyskinesia. In severe cases, a specific antidyskinetic drug may be indicated (e.g. tetrabenazine may be worth trying). Benzodiazepines, baclofen and valproate have also been used with some success.

PARKINSONISM

This is the commonest extrapyramidal effect charac-terised by lack (akinesia) or slowness (bradykinesia) of movement, muscle rigidity and tremor. The patient has an expressionless face, speaks monotonously, develops a coarse tremor of the hands and can have difficulty in swallowing. It closely resembles the idiopathic form of the disease. Symptoms usually develop within days or weeks of starting antipsychotic treatment or after a recent increase in dose. Elderly patients are particularly susceptible to iatrogenic parkinsonism, especially those with dementia. The condition responds to lowering the dose of antipsychotic or treatment with an antimuscarinic drug (e.g. procyclidine or orphenadrine).

DRUGS ASSOCIATED WITH EXTRAPYRAMIDAL REACTIONS

Extrapyramidal reactions are associated with dopamine receptor antagonists, which include antipsychotic and antiemetic drugs (Table 14.5). High-potency (relatively high dopamine D₂ activity and low antimuscarinic activity) and depot antipsychotics have been particularly implicated. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) have also caused acute reactions. Other drugs occasionally reported to produce extrapyramidal reactions include anticonvulsants (carbamazepine) and methyldopa.

Table 14.5 Some drugs associated with extrapyramidal reactions

Drug group	Example(s)
Antipsychotics	Chlorpromazine
	Flupentixol (flupenthixol)
	Fluphenazine
	Haloperidol
	Risperidone
	Trifluoperazine
Antiemetics	Metoclopramide
	Prochlorperazine
Antidepressants	Tricyclics (e.g. amitriptyline)
Selective serotonin reuptake inhibitors	Paroxetine

CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

The phenothiazine group comprises a large proportion of the antipsychotics. This group can be divided into three subgroups with respect to the chemical side chain of the molecule. By altering the side chain, new molecules were formed, but this influenced the side-effect profile with particular regard to sedative effects, antimuscarinic effects and extrapyramidal side-effects (Table 14.6).

Table 14.6 Adverse effects of phenothiazines

ALIPHATIC PHENOTHIAZINES (GROUP 1)

Chlorpromazine was the first antipsychotic to be introduced, in 1952. It is used for a wide range of indications, including control of disturbed behaviour and psychotic symptoms, and control and maintenance of schizophrenia and other psychoses. Chlorpromazine is also used to treat nausea, vomiting and intractable hiccup. Photosensitisation is more common with chlorpromazine than with other antipsychotics. Promazine is indicated for agitation, restlessness and anxiety, especially in the elderly. It is not sufficiently active by mouth to be used as an antipsychotic drug.

PIPERIDINE PHENOTHIAZINES (GROUP 2)

Pericyazine can be used for the control of disturbed behaviour, schizophrenia and other psychoses. Pipotiazine is available only as an intramuscular injection. It is fairly sedative, with a relatively low potential for causing extrapyramidal reactions, as it has pronounced antimuscarinic activity.

PIPERAZINE PHENOTHIAZINES (GROUP 3)

Fluphenazine is used as a depot formulation. Trifluoperazine is commonly used in paranoia, but its use is limited due to the high incidence of extrapyramidal side effects.

NON-PHENOTHIAZINES

The non-phenothiazines (Box 14.1) tend to have adverse effects similar to those of the phenothiazines group 3 (piperazine phenothiazines), i.e. they are generally characterised by fewer sedative and fewer antimuscarinic effects but more pronounced extrapyramidal effects.

Box 14.1 The non-phenothiazine antipsychotic drugs

• Butyrophenones:

• benperidol, haloperidol

• Diphenylbutylpiperidines:

• pimozide

• Thioxanthenes:

• flupentixol, zuclopenthixol

BUTYROPHENONES

Benperidol is used for the control of deviant anti-social sexual behaviour resulting from mental illness. However, its value has not been established. Haloperidol is a widely used antipsychotic and is possibly the drug of choice for acute mania. It is less sedating than chlorpromazine but has more pronounced extrapyramidal side effects.

DIPHENYLBUTYLPIPERIDINES

These are long-acting antipsychotics. Pimozide is long-acting and less sedating than chlorpromazine. An electrocardiogram (ECG) is required prior to commencing treatment and at regular intervals if doses greater than 16 mg daily are being prescribed.

THIOXANTHENES

These have activity similar to that of the piperazine phenothiazines. Flupentixol (flupenthixol) is indicated for schizophrenia and other psychoses, except when there is mania or motor hyperactivity or in confusional states; it is also useful in low doses in depression. It is used mainly as depot injections. Zuclopenthixol is indicated for schizophrenia, especially with agitated, aggressive or hostile behaviour. It too is used mainly as depot injections. Zuclopenthixol acetate injection is useful for the short-term management of acute psychosis and mania.

SUBSTITUTED BENZAMIDES

This is a structurally distinct group of drugs with a lower incidence of side-effects, particularly tardive dyskinesia. Sulpiride, at high doses, can control positive symptoms; at lower doses (less than 800 mg per day), it has an alerting effect useful for the treat-ment of negative symptoms.

Antipsychotics, type and dosage, are illustrated in Table 14.7.

Table 14.7 Antipsychotics: type and dosage

Drug type	Drug	Oral dose
Butyrophenones	Benperidol	0.25–1.5 mg daily in divided doses
	Haloperidol	Initially 1.5–3 mg two or three times daily or 3–5 mg two or three times daily in severely affected or resistant patients; in resistant schizophrenia, up to 30 mg daily
Diphenylbutylpiperidine	Pimozide	2–20 mg daily
Phenothiazines	Chlorpromazine	Initially 25 mg three times daily; usual maintenance dose, 75–300 mg daily; maximum dose, 1 g daily
	Levomepromazine (methotrimeprazine)	Initially 25–50 mg daily in divided doses, increased as necessary to 1 g daily
	Promazine	100–200 mg four times daily; agitation and restlessness in the elderly, 25–50 mg up to four times daily
Piperazine phenothiazines	Fluphenazine	Initially 2–10 mg daily in two or three divided doses adjusted according to response to 20 mg daily
	Perphenazine	Initially 4 mg three times daily to a maximum of 24 mg daily
	Trifluoperazine	Initially 5 mg twice daily increased by 5 mg according to response
Piperidine phenothiazines	Pericyazine	Initially 75 mg daily in divided doses to a maximum of 300 mg daily
Substituted benzamide	Sulpiride	200–400 mg twice daily, maximum of 800 mg daily in patients with predominantly negative symptoms and 2.4 g daily in patients with mainly positive symptoms
Thioxanthenes	Flupentixol	3–9 mg twice daily, maximum 18 mg daily
	Zuclopenthixol	Initially 20–30 mg daily in divided doses to a maximum of 150 mg daily

ATYPICAL ANTIPSYCHOTICS

All conventional antipsychotics are targeted primarily at the D₂ receptor and are effective against positive symptoms (delusions and hallucinations) but have little impact on negative symptoms (e.g. lack of motivation and social withdrawal) and have potentially debilitating side-effects. These are very distressing for patients and contribute to poor compliance with treatment. It has been estimated that 40–65% of schizophrenic patients will discontinue oral antipsychotic therapy within 6 weeks of starting treatment, mainly because of extrapyramidal side effects.

In recent years, several new antipsychotic drugs, termed atypical antipsychotics because of their low propensity for causing extrapyramidal symptoms, have been introduced. The first was clozapine, which differs from conventional antipsychotics in having a relatively weak affinity for D₂ receptors while affecting a number of other neuroreceptors (serotonergic, histaminergic, muscarinic, adrenergic). It improves both positive and negative symptoms and reduces hostile and aggressive behaviour and suicidality. Clozapine causes few extrapyramidal symptoms. However, the risk of neutropenia in the first year of treatment is 2–3%, and haematological monitoring is a mandatory condition of treatment. Initiation must be as a hospital in-patient. Leucocyte and differential blood counts must be normal before treatment commences and must be monitored weekly for the first 18 weeks, then fortnightly. Patients who have received clozapine for a year or more and have stable blood counts may have their blood monitoring reduced to every 4 weeks. Drugs that depress leucopoiesis (such as carbamazepine) should be avoided. Conventional antipsychotics should be tapered off before starting clozapine. The dose of clozapine should be titrated gradually upwards, with the patient being observed for side-effects, including:

• postural hypotension (due to a-adrenergic block)

• sedation (due to histaminergic block)

• tachycardia (due to muscarinic block)

• fever (may be due to neutropenia but usually unexplained and settles despite continued treatment).

Excess sedation sometimes responds to alterations in the timing of the daily dose. For example, early morning hangover may be reduced by giving the last dose of the day at 8 p.m. Care should be taken to distinguish true drug-induced sedation from lack of motivation, often seen in schizophrenia, or simple inactivity due to boredom. Hypersalivation can be alleviated by simple measures such as propping up the pillows at night, although antimuscarinic medication is usually required. When postural hypotension occurs, the patient should be advised not to stand up quickly. Dietary advice and exercise may be helpful to avoid constipation and weight gain. Seizures are dose-related, and the incidence may be increased by the rapid upwards titration of the dose – hence it is important to increase the dose slowly. Tachycardia, when persistent, can be alleviated by beta-blockers.

The dose regimen for clozapine is 12.5 mg once or twice on the first day then 25–50 mg on the second day, and then, if well tolerated, gradually increased in steps of 25–50 mg over 14–21 days to 300 mg daily in divided doses (larger dose at night, up to 200 mg daily may be taken as a single dose at bedtime). If necessary, there may be further increased steps of 50–100 mg once (preferably) or twice weekly. The usual antipsychotic dose is 200–450 mg daily (maximum 900 mg daily), with subsequent adjustment to usual maintenance of 150–300 mg. Lower doses should be used in the elderly and special risk groups. Other atypical antipsychotics include risperidone, olanzapine, quetiapine, amisulpride, zotepine, aripiprazole and sertindole.

Changing to an atypical antipsychotic is not necessary if a conventional antipsychotic controls symptoms adequately and the individual does not suffer unacceptable side-effects. The atypical antipsychotics should be considered:

• when choosing first-line treatment of newly diagnosed schizophrenia

• for an individual who is suffering unacceptable side-effects from a conventional antipsychotic

• for an individual in relapse whose symptoms were previously inadequately controlled.

There are subtle differences in the mode of action of the atypical antipsychotics. As a result, a patient who is doing less well while prescribed one of the atypicals may fare better when changed to another. Risperidone, for example, binds strongly to the 5-HT₂ receptor and less strongly to the D₂, histamine H₁, and α₁– and α₂-adrenergic receptors. The main clinical features of risperidone are thought to be due to its balance of 5-HT₂ and D₂ receptor antagonism. As a D₂ antagonist, risperidone relieves positive symptoms by countering the dopaminergic overactivity that causes them. 5-HT₂ antagonism may reduce negative and affective symptoms. Antagonism at 5-HT₂ receptors modifies dopaminergic transmission, reducing the effect of D₂ antagonism and lowering the risk of extrapyramidal side effects. α₁-adrenergic receptor antagonism may cause hypotension. α₂-adrenergic receptor antagonism may reduce the sedative effect.

Olanzapine and quetiapine bind to similar receptors as risperidone, whereas amisulpride, which also has a high affinity with dopaminergic receptors, has no affinity for serotonin and histaminergic receptors.

The atypical antipsychotics are well absorbed. Side-effects include weight gain, dizziness, postural hypotension (especially during initial dose titration) and extrapyramidal symptoms (usually mild and respond to dose reduction or an antimuscarinic drug), and occasionally tardive dyskinesia on long-term administration. Table 14.8 provides doses of atypical antipsychotic drugs.

Table 14.8 Atypical antipsychotics: dosages

Drug	Oral dose(s)
Amisulpride	400–800 mg daily in two divided doses for acute episode
	50–300 mg for negative symptoms
Aripiprazole	15–30 mg daily
Clozapine	Titrated by 25-mg increments to 200–500 mg daily
Olanzapine	5–20 mg daily
Quetiapine	300–450 mg daily in two divided doses
Risperidone	4–6 mg daily
Sertindole	12–20 mg single dose
Zotepine	Up to 100 mg three times daily