Mode Of

Since the potency (therapeutic efficacy in relation to weight) of antipsychotic agents varies markedly between compounds, it is useful to think of the effective antipsychotic dose of classical agents in terms of 'chlorpromazine equivalents' (see Table 19.5). For example, haloperidol has a relatively high antipsychotic potency, such that 2-3 mg is equivalent to chlorpromazine 100 mg, whereas sulpiride 200 mg (low potency) is required for the same antipsychotic effect.

Patients who are 'neuroleptic naive' (i.e. have never previously taken any antipsychotic agent) should start at the lowest available dosage, such as haloperidol 0.5 mg/day or chlorpromazine 25 mg/ day, in case the patient is particularly susceptible to adverse effects, especially extrapyramidal motor symptoms. Conservative starting doses are also recommended in the elderly and for patients with learning disabilities who may require antipsychotics for psychosis or severe behavioural disturbance. The dose can be titrated up at intervals, until the desired effect in treating psychotic symptoms, calming disturbed behaviour or effecting sedation is achieved. The interval depends on the context, with the urgency of the situation and previous use of antipsychotics being factors which would accelerate the upward titration. An important issue is that the longer a psychosis is left untreated the less favourable is the outcome; thus drug treatment should be instigated as soon as an adequate period of assessment has allowed a provisional diagnosis to be established.

For each antipsychotic agent there is a licensed maximum dose; for example up to 1000 mg of chlorpromazine/day may be given under the United Kingdom licence. Prescribing beyond the licensed maximum dose requires specialist consent. When two antipsychotics are co-prescribed, the maximum antipsychotic dose should not exceed 1000 mg of chlorpromazine equivalents/day except under specialist supervision. For some antipsychotics the licenced maximum dose is considerably less than 1000 mg of chlorpromazine equivalents/day. For instance, the licenced maximum dose of thioridazine was reduced to 600 mg/day following concerns about its cardiovascular toxicity. Note

TABLE 19.4 Symptoms of schizophrenia

Positive symptoms

Negative symptoms

Hallucinations, most commonly auditory (i.e. voices) in the 3rd person, which patients may find threatening.The voices may also give commands.Visual hallucinations are rare.

Dc/usrons, most commonly persecutory. 'Passivity phenomena' include delusions of thought broadcasting, thought insertion or thought withdrawal, made actions, impulses or feelings.

bizarre behavtours including agitation, sexual disinhibition. repetitive behaviour, wearing of striking but inappropriate clothing.

Thought disorder manifest by failure in the organisation of speech such that it drifts away from the point (tangentiality), never reaches the point (circumstantiality), moves from one topic to the next illogically (loosened associations, knight's move thinking), breaks off abruptly only to continue on an unrelated topic (derailment) or moves from one topic to the next on the basis of a pun or words which sound similar (clang association).

Affective flattening manifest by unchanging facial expression with lack of communication through expression, poor eye contact, lack of responsiveness, psychomotor slowing

Aiogia (literally'absence of words' manifesting clinically as a lack of spontaneous speech (poverty of speech),

Anhedonia (inability to derive pleasure from any activity) and Associahty (narrowing of repertoire of interests and impaired relationships)

ApaihyiAvolution involving lack of energy, lack of motivation to work, participate in activities or initiate any goal-directed behaviour,and poor personal hygiene. jAtienuon prob/ems involving an inability to focus on any one issue or engage fully with communication.

that plasma electrolytes and an ECG should be checked on introducing or increasing the dose of thioridazine and that an ECG should be seen before prescribing pimozide and sertindole.

Prescription of atypical antipsychotics follows similar rules to those for classical drugs, starting at low doses in neuroleptic naive patients. Whereas there is a wide range of effective doses for many classical agents (e.g. chlorpromazine 25-1000 mg/ day), much narrower ranges have been defined for atypical agents (Table 19.5). While classical antipsychotics are licenced for the management of acutely disturbed behaviour as well as for schizophrenia, atypical agents are generally licenced only for the latter indication, although that for risperidone is broader. For most atypical agents used in schizophrenia, a brief period of dose titration by protocol up to a stated lowest therapeutic dose is usual, e.g. risperidone 4 mg/day, quetiapine 300 mg/day. Dose increases are indicated where there is no response after 2 weeks and these may be repeated until the maximum licenced dose is achieved.

Clozapine may be initiated only under specialist supervision and only after two other antipsychotic agents have failed through lack of efficacy or adverse effects. Additionally, leucocyte count monitoring is mandatory (danger of agranulocytosis) and blood pressure checking is required (for hypotensive effect). Patients are most vulnerable to agranulocytosis on initiation of therapy with 75% of cases occurring in the first 18 weeks. The dose titration schedule must be followed strictly, starting with clozapine 12.5 mg nocte and working up over a period of four weeks to a target therapeutic dose of 450 mg/day.

Alternative administration strategies in acute use of antipsychotics

Some of the antipsychotics are available as intramuscular injections for patients who are unable or unwilling to swallow tablets (as is common in psychosis or severe behavioural disturbance). Halo-peridol is most often used for these indications on psychiatric inpatient wards (chlorpromazine i.m. being restricted due to hypotension and skin nodule formation). Olanzapine may be given i.m.

for acute behavioural disturbance in schizophrenia. This drug is also presented as a 'velotab' which dissolves rapidly on contact with the tongue allowing drug to be absorbed despite lack of cooperation from a disturbed patient.

Long-acting (depot) injections

Haloperidol, zuclopenthixol, fluphenazine, flupentixol and pipothiazine are available as depot intramuscular injections for maintenance treatment of patients with schizophrenia and other chronic psychotic disorders. Provided the patient is willing to agree to have depot injections, usually by a community psychiatric nurse at intervals of 2-4 weeks, the need to take tablets two or three times a day is removed. Poor compliance with oral medication is the most common cause of admission to hospital with a relapse of schizophrenia. A reduced initial dose of the depot medication should be given, with a review for unwanted effects after 5-10 days.

Rapid tranquillisation

Rapid tranquillisation protocols have been devised for patients who are severely disturbed and violent or potentially violent and have not responded to nonpharmacological approaches. The risks from administering psychotropic drugs (e.g. cardiac arrhythmia with high-dose antipsychotics) may greatly outweigh the risk of leaving the patient untreated, including physical trauma and the consequences of over-stressing the cardiovascular system.

A benzodiazepine, e.g. lorazepam 1-2 mg i.v. (into a large vein) failing which i.m. (dilute with an equal volume of water or physiological saline) is the first option if the patient is not already receiving an antipsychotic drug. Patients requiring rapid tranquillisation are commonly taking antipsychotics for established illness and an additional antipsychotic may then be used if the patient has not received an adequate dose; otherwise a benzodiazepine should given. Haloperidol 2-10 mg i.m. is currently preferred for rapid tranquillisation, but new protocols may evolve with the development of atypical antipsychotics that can be given i.m. When i.m. antipsychotic or benzodiazepine tranquilliser is given as an emergency, pulse, blood pressure, temperature and respiration should be monitored, and pulse oximetry (oxygen saturation) if consciousness is lost.

When at least two doses of haloperidol i.m. fail to produce the desired result, zuclopenthixol acetate i.m. is an alternative. This heavily sedating drug usually produces a calming effect within 2 h, persisting for 2-3 days if used at appropriate dose. Zuclopenthixol acetate should never be prescribed to the neuroleptic naive. Patients must be observed with the utmost care following administration. Some will require a second dose within 1-2 days.

Amylobarbitone and paraldehyde have a role in emergencies when antipsychotic and benzodiazepine options have been exhausted.

ADVERSE EFFECTS (see Table 19.5)

Active psychotic illnesses often cause patients to have poor insight into their condition; unwanted drug effects can compromise already fragile compliance and lead to avoidable relapse.

Classical antipsychotics

It is rare for any patient taking classical antipsychotic agents completely to escape their adverse effects. Thus it is essential to discuss with patients the possibility of unwanted effects and regularly to review this aspect of their care.

Extrapyramidal symptoms. All classical antipsychotics are capable of producing these effects because they act by blocking dopamine receptors in the nigrostriatal pathway. The result is that some 75% of patients experience extrapyramidal symptoms which may appear shortly after starting the drug or increasing its dose (acute effects), or some time after a particular dose level has been established (tardive effects, see p. 387).

Acute extrapyramidal symptoms. Dystonias are manifest as abnormal movements of the tongue and facial muscles with fixed postures and spasm, including torticollis and bizarre eye movements ('oculogyric crisis'). Parkinsonian symptoms result in the classical triad of bradykinesia, rigidity and tremor. Both dystonias and parkinsonian symptoms are believed to result from a shift in favour of cholinergic rather than dopaminergic neurotransmission in the nigrostriatal pathway (see p. 422). Anticholinergic agents, e.g. procyclidine, orphe-nadrine or benztropine, restore the balance in favour of dopaminergic transmission but are liable to provoke antimuscarinic effects (dry mouth, urine retention, constipation, exacerbation of glaucoma and confusion) and they offer no relief for tardive dyskinesia, which may even worsen. They should be used only in response to clear dystonic or parkinsonian symptoms rather than for prophylaxis. Benzodiazepines, with their general inhibitory effects, are an alternative. Thioridazine and related Type 2 phenothiazines are less likely to provoke extrapyramidal effects as they also block cholinergic transmission (but patients may suffer antimuscarinic effects). Note that confusion from anticholinergic effects may mimic or complicate schizophrenic thought disorder.

Akathisia is a state of motor and psychological restlessness, in which patients exhibit persistent foot tapping, moving of legs repetitively and being unable to settle or relax. A strong association has been noted between its presence in treated schizophrenics and subsequent suicide. A P-adrenoceptor blocker is the best treatment, although anticholinergic agents may be effective where akathisia coexists with dystonias and parkinsonian symptoms. Differentiating symptoms of psychotic illness from adverse drug effects is often difficult: drug-induced akathisia may be mistaken for agitation induced by psychosis.

Tardive dyskinesia affects about 25% of patients taking classical antipsychotic drugs, the risk increasing with length of exposure. It was formerly thought to be a consequence of up-regulation or supersensitivity of dopamine receptors. A preferred explanation is that tardive dyskinesia is a consequence of oxidative damage after neuroleptic-induced increases in glutamate transmission. Patients display a spectrum of abnormal movements from minor tongue profusion, lip-smacking, rotational tongue movements and facial grimacing, choreo-athetoid movements of the head and neck and even to twisting and gyrating of the whole body. It is less likely to remit on stopping the causative agent than

Key: CPZ equiv dose = Chlorpromazine equivalent dose.This concept is of value in comparing the potency of classical antipsychotics. Dose ranges are not specified as they are extremely wide and drugs are normally titrated up from low starting doses (e.g. chlorpromazine 25 mg or equivalent) until an adequate antipsychotic effect is achieved or the maximum dose reached.The chlorpromazine equivalent dose concept is of less value for atypical antipsychotics since minimum effective doses (Min. eff. dose) and narrower therapeutic ranges have been defined. Maximum dose (Max. dose) can be exceeded only under specialist supervision.

* The maximum recommended dose of thioradazine was reduced to 300 mg/day (or 600 mg/day in hospitalised patients) following concerns about QT prolongation and risk of fetal cardiac arrhythmias at higher doses. ** A dose of clozapine 50 mg is considered equivalent to chlorpromazine 100 mg.

U Lower doses of amisulpride (e.g. 100 mg/day) are indicated for patients with negative symptoms of schizophrenia only.

TABLE 19.5 Relative frequency of selected adverse effects of antipsychotic drugs
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